leukemia committee - swog 2019/rosbook... · 2019. 3. 20. · leukemia in their peripheral blood or...

APRIL 24 - 27, 2019 SWOG LEUKEMIA 1

LEUKEMIA COMMITTEE


CONTENTS

S1204 Surveillance ........................................................................................................................................................ 6

S1312 Phase I ................................................................................................................................................................ 8

S1318 Phase I-II .......................................................................................................................................................... 13

S1612 Phase II-III ........................................................................................................................................................ 19

S1712 Phase II ............................................................................................................................................................. 25


Patient Registrations to Studies

by 12 Month Intervals

LEUKEMIA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded.

SWOG LAPS MEMBER NCORP NON-SWOG

446

600

403

110

64

134

0

100

200

300

400

500

600

700

Time of Registration

Jan 2013Dec 2013

Jan 2014Dec 2014

Jan 2015Dec 2015

Jan 2016Dec 2016

Jan 2017Dec 2017

Jan 2018Dec 2018

101

87

51

207

151

130

63

256

68

135

66

134

54 4337


Patient Registrations by Study and Arm LEUKEMIA COMMITTEE

Jul 2018

Dec 2018

Jan 2018

Jun 2018

Jul 2017

Dec 2017

All

Patients

S1312 ALL, CD22+, REL/REF, Inotuzumab+CVP

Initial Registration

CVP + Inotuzumab dose level 1 0 0 0 5





CVP + Inotuzumab MTD 7 2 0 9

7 2 1 46

S1318 ALL, Age 65+, Ph±, Blinatumomab

Initial registration

Induction: Ph- 0 0 4 31

Induction: Ph+/Ph-like 0 0 0 16

0 0 4 47

S1612 AML/MDS, Age 60+, Aza/Novel Therapeutics

Specimen Submission

FLT3 Testing 67 46 0 113

Randomization

Azacitidine 14 12 0 26

Azacitidine + Nivolumab 16 10 0 26

Azacitidine + Midostaurin 14 12 0 26

44 34 0 78

S1712 CML, Chronic Phase, TKI +/- Ruxolitinib

Randomization

Single Agent TKI 1 0 0 1

TKI + Ruxolitinib 1 0 0 1

2 0 0 2


Non-SWOG Studies with SWOG-Credited Registrations LEUKEMIA COMMITTEE

Studies with Accrual from July 2017 - December 2018

SWOG Accrual

SWOG

Champion

Jul 2018

Dec 2018

Jan 2018

Jun 2018

Jul 2017

Dec 2017

SWOG

Total

Total

Accrued

E1910 BCR-ABL-neg, B ALL, Blinatumomab M Liedke 15 16 9 102 388

Date Activated: 12/23/13

Most Recent Progress Report

NHLBIMDS LEUK, National MDS Study D Hill, C Yi 6 8 1 19 610

Date Activated: 04/05/16

No Progress Report Available


S1204

S1204 Surveillance

A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for

Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and

Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients

Study Chairs:

S Ramsey, D Hershman

Statisticians:

J Unger, K Arnold

Data Coordinator:

M Yee

Date Activated:

08/29/2013

Date Closed:

02/15/2017

Objectives Among newly diagnosed cancer patients presenting

to SWOG-affiliated community and academic

oncology clinics, estimate the prevalence of human

immunodeficiency virus (HIV), hepatitis B (HBV),

and hepatitis C (HCV) infection.

Evaluate known sociodemographic, clinical, and

behavioral factors that are significantly associated

with previously undiagnosed HIV, HBV, and/or

HCV infection in a population of people with newly

diagnosed cancer

Among patients who are identified as having HIV,

HBV, and/or HCV, describe the timing and type of

treatments received (if any), both for the viral

infections and the cancers.

Describe the type of adverse events possibly

attributable to the patient's viral status in patients

with HIV, HBV, and/or HCV infection.

Using simulation modeling that is directly informed

by the data obtained from this study, determine the

cost-effectiveness (expressed as cost per infection

detected and cost per year of life gained) of (1)

routine, universal screening and (2) risk factor-

directed screening of newly diagnosed cancer

patients for HIV, HBV and/or HCV versus current

care.

Patient Population Patients must be presenting for evaluation or

treatment for the first diagnosis of a new solid or

hematologic cancer malignancy. Confirmed diagnosis

date must be within 120 days prior to first clinic visit

as a newly diagnosed cancer patient at the registering

clinic. Patients presenting for "second opinions" of

confirmed malignancies are eligible, including those

who have started cancer treatment at other facilities.

Patients must be registered within 90 days after their

first clinic visit. Patients must not have been

diagnosed with a malignancy other than the current

malignancy within the past five years, with the

exception of basal cell or squamous cell skin cancer,

in situ cervical cancer, or in situ breast cancer.

Patients must have no evidence of disease for a prior

malignancy for at least five years prior to

randomization except as noted above.

Patients must be 18 years of age or older. Patients

must have had their blood drawn for viral status

testing for HIV, HBV and HCV or provide

acceptable viral status documentation prior to

registration, as defined in the protocol. Note that

patients must have blood drawn for testing prior to

registration for any of the three viruses not covered

by the documentation. Patients are allowed to

participate in other clinical trials.

Accrual Goals A total of 3,061 patients will be accrued to achieve

3,000 eligible patients.


S1204

Summary Statement For the current status of this study, please refer to the

Cancer Care Delivery chapter.


S1312/I

S1312 Phase I

A Phase I Study of Inotuzumab (NSC-772518) in Combination with CVP

(Cyclophosphamide, Vincristine, Prednisone) for Patients with

Relapsed/Refractory CD22-Positive Acute Leukemia (including B-ALL,

Mixed Phenotypic Leukemia, and Burkitt's Leukemia)

Study Chairs:

A Advani, M Liedtke

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

04/01/2014

Objectives To assess the safety of inotuzumab in combination

with cyclophosphamide, vincristine and prednisone

(CVP) and to determine the maximum tolerated dose

(MTD) of inotuzumab in this regimen for patients

with relapsed or refractory CD22-positive acute

leukemia (B-ALL, mixed phenotype, and Burkitt's).

To estimate the preliminary activity [response rate:

complete remission (CR) + complete remission with

incomplete count recovery (CRi)] of this combination

in the expansion cohort.

To estimate the frequency and severity of toxicities

of this combination in this patient population.

Patient Population Patients must have a diagnosis of relapsed or

refractory CD22-positive acute leukemia including

B-ALL, mixed phenotype leukemia (bilineal and

biphenotypic), or Burkitt's leukemia based on WHO

classification. Patients with bilineal leukemia are

excluded. Patients must have evidence of acute

leukemia in their peripheral blood or bone marrow.

Patients must have ≥ 5% blasts in the peripheral

blood or bone marrow. At least ≥ 20% of those blasts

must be CD22-positive (surface) based on local

immunophenotyping and histopathology. Patients

must be refractory or have relapsed following prior

induction therapy.

Patients may have received prior allogeneic

transplant or autologous transplant. Patients with

prior allogeneic bone marrow transplant will be

eligible only if the conditions stated in the protocol

are met. Patients known to have Ph+ ALL must have

either failed treatment or been intolerant to treatment

with at least one second or third generation tyrosine

kinase inhibitor. Patients must not have received

prior treatment with inotuzumab. Previous treatment

with other anti-CD22 antibodies must have been

completed at least 90 days prior to registration.

Patients must not have received any chemotherapy,

investigational agents, or undergone major surgery

within 14 days prior to registration with the following

exceptions: (1) Monoclonal antibodies must not have

been received for one week prior to registration; (2)

Chimeric antigen receptor (CAR) T-cells must not

have been received for 28 days prior to registration;

(3) Steroids, hydroxyurea, vincristine, 6-

mercaptopurine, methotrexate, thioguanine and

intrathecal chemotherapy are permitted within any

time frame prior to registration. FDA-approved

tyrosine kinase inhibitors may also be administered

until one day prior to start of study therapy (C1, D1).

All drug-related toxicities must have resolved to ≤

Grade 2. Treatment with hydroxyurea and steroids is

permitted to bring down peripheral blast count.


S1312/I

Patients must be at least 18 years of age and have

Zubrod performance status of 0-2. Patients must not

have a systemic bacterial, fungal, or viral infection

that is not controlled. Patients must not have active

CNS involvement. Patients must have < Grade 2

neuropathy (sensory/motor). Patients must not have a

history of chronic or active hepatitis B or C infection.

Patients must not have evidence or history of veno-

occlusive disease or sinusoidal obstruction syndrome.

Patients who are known to be HIV+ are eligible

providing they meet all of the criteria in the protocol.

Patients with a history of a serious allergic or

anaphylactic reaction to humanized monoclonal

antibodies are not eligible. Patients must have

adequate hematologic, renal, hepatic, and cardiac

function.

Accrual Goals Patient enrollment will follow the traditional "3+3"

algorithm until the MTD for inotuzumab is reached

or the highest dose tested is judged tolerable. This

study will accrue 3-30 eligible and evaluable patients

in the Phase I portion and 12 additional eligible

patients in the expansion cohort.

Summary Statement The Phase I portion of this study evaluated five dose

levels of inotuzumab. Dose level 5 (0.8 mg/m2 on day

1 and 0.5 mg/m2 on days 8 and 15) was established as

the maximum tolerated dose (MTD) for the

expansion cohort. The following summary includes

patients treated at dose level 5 of the Phase I portion

of the trial as well as patients in the expansion cohort,

also treated at dose level 5.

The fifth dose level of inotuzumab closed on July 31,

2017 with 11 patients registered. Five patients went

off treatment before their counts recovered and

before prolonged myelosuppression could be ruled

out and are therefore not evaluable for DLT. One

patient experienced DLT: Grade 3 ascites, an event

considered clinically significant regardless of

duration. There were no Grade 4 or Grade 5 non-

hematological toxicities related to treatment at dose

level 5.

After establishing the MTD as dose level 5, the

expansion cohort opened to accrual on October 25,

2017. As of December 31, 2018, nine patients have

registered to the expansion cohort. Of these nine, one

patient experienced Grade 4 treatment-related febrile

neutropenia and Grade 4 treatment-related sepsis. No

other Grade 4 or 5 treatment-related non-

hematological toxicities have been reported. Though

the MTD has been established and toxicities in this

cohort are not dose limiting, we will describe DLTs

in the expansion cohort to better understand toxicities

at this dose. One patient in the expansion cohort is

not evaluable for DLT because they went off

treatment before their counts recovered and before

prolonged myelosuppression could be ruled out.

None of the six patients evaluable for DLT has

experienced a DLT as of February 1, 2019.

In all, 12 patients went off treatment at dose level 5

for non-protocol specified reasons, due to lack of

treatment benefit (4) or to receive transplant (8).

Registration by Institution

Registrations ending December 31, 2018

Institutions Total Reg

City of Hope Med Ctr 17

Cleveland Clinic OH 11

Rochester, Univ of 9

Baylor College 7

Stanford University 2

Total (5 Institutions) 46


S1312/I

Registration, Eligibility, and Evaluability

Registrations ending December 31, 2018; Data as of February 1, 2019

TOTAL

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab

MTD

NUMBER REGISTERED 46 5 5 11 5 11 9

INELIGIBLE 2 0 1 1 0 0 0

ELIGIBLE 44 5 4 10 5 11 9

Analyzable, Pend. Elig. 2 0 0 0 0 0 2

RESPONSE ASSESSMENT

Determinable 41 5 4 8 5 11 8

Not Determinable 2 0 0 2 0 0 0

Too Early 1 0 0 0 0 0 1

ADVERSE EVENT ASSESSMENT

Evaluable 44 5 4 10 5 11 9

DLT ASSESSMENT

Evaluable 25 3 3 6 3 6 6

Not Evaluable 15 2 1 4 2 5 1

Too Early 2 0 0 0 0 0 2

Patient Characteristics


CVP +

Inotuzumab

dose level 5

(n=11)

CVP +

Inotuzumab MTD

(n=9)

AGE

Median 37.9 40.7

Minimum 25.0 21.6

Maximum 58.7 79.8

SEX

Males 6 55% 6 67%

Females 5 45% 3 33%

HISPANIC

Yes 3 27% 3 33%

No 6 55% 5 56%

Unknown 2 18% 1 11%

RACE

White 7 64% 4 44%

Black 1 9% 0 0%

Asian 1 9% 3 33%

Unknown 2 18% 2 22%


S1312/I

Treatment Summary


TOTAL

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab MTD

NUMBER ON PROTOCOL TREATMENT 3 0 3

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

17 11 6

Treatment completed as planned 1 0 1

Adverse Event or side effects 3 1 2

Progression/relapse 1 0 1

Other - not protocol specified 12 10 2

MAJOR PROTOCOL DEVIATIONS 0 0 0

LOST TO FOLLOW-UP 0 0 0

CONSENT WITHDRAWAL AFTER

TREATMENT INITIATION

0 0 0

Number of Patients with a Given Type and Grade of Adverse Event

Adverse Events Unlikely or Not Related to Treatment Excluded

Hematologic Adverse Events Only

Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed


CVP + Inotuzumab dose

level 5

(n=11)

Grade

CVP + Inotuzumab MTD

(n=9)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5

Anemia 6 5 0 0 8 1 0 0

Lymphocyte count decreased 5 2 4 0 5 2 2 0

Neutrophil count decreased 3 4 4 0 3 1 5 0

Platelet count decreased 6 1 4 0 2 2 5 0

White blood cell decreased 4 1 6 0 2 0 7 0

MAX. GRADE ANY ADVERSE

EVENT

0 3 8 0 1 1 7 0


S1312/I



Non-Hematologic Adverse Events Only



CVP + Inotuzumab dose

level 5

(n=11)

Grade

CVP + Inotuzumab MTD

(n=9)

Grade


Ascites 10 1 0 0 8 1 0 0

Enterocolitis 10 1 0 0 9 0 0 0

Febrile neutropenia 10 1 0 0 4 4 1 0

Hyperglycemia 9 2 0 0 9 0 0 0

Hypertension 11 0 0 0 8 1 0 0

Infections/infestations-Other 10 1 0 0 7 2 0 0

Lipase increased 11 0 0 0 8 1 0 0

Mucositis oral 11 0 0 0 8 1 0 0

Sepsis 11 0 0 0 8 0 1 0


EVENT

8 3 0 0 3 5 1 0


S1318/I-II

S1318 Phase I-II

Coordinating Group: SWOG

A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone,

Vincristine, Methotrexate, 6-Mercaptopurine) for Patients ≥ 65 Years of Age with

Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic

Leukemia (ALL) and of Dasatinib (NSC-732517), Prednisone and Blinatumomab

for Patients ≥ 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome

Positive (Ph+) ALL, Relapsed/Refractory Philadelphia-Chromosome Positive

(Ph+) ALL, and Philadelphia-Chromosome-Like Signature (Ph-Like) ALL (Newly

Diagnosed or Relapsed/Refractory) with Known or Presumed Activating

Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF)

Participants:

SWOG, CTSU (Supported by Alliance and ECOG-ACRIN)

Study Chairs:

A Advani, K O'Dwyer, M Wiedewult (Alliance), J Park

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

Date Activated:

01/12/2015

Date Closed*:

04/15/2017

*Temporary closure

SCHEMA

REGISTRATION Step 1

D28 CR/CRi?

Dasatinib / Prednisone Induction

Continue Induction Cycle

YES

Blinatumomab

Re-induction 1

Ph-positive/Ph-like DSMKF Patients

NO

Until intolerance or progression for up to 10 years from registration, then

Protocol Therapy Complete

CR/CRi?

YES

NO

Off Protocol Therapy

REGISTRATION Step 2: Post-remission therapy

Blinatumomab/Dasatinib

REGISTRATION Step 3: Maintenance

Dasatinib/Prednisone

Ph-negative Patients:

Blinatumomab Induction

CR/CRi?

REGISTRATION Step 1

YES NO

REGISTRATION Step 2:

Post-remission therapy

Blinatumomab

Continued CR/Cri?

REGISTRATION Step 3:

Maintenance

POMP Chemotherapy

Protocol Therapy Complete

Blinatumomab

Re-induction

D56 CR/CRi?

YESNO

Continue Dasatinib

to Day 84

Continued CR/Cri?

YES

Blinatumomab

Re-induction 2

CR/CRi?

NO

YESYES

Continued CR/Cri?

NO

NO

CR/CRi?

YES NO

Off Protocol Therapy

YES NO


S1318/I-II

Objectives To evaluate the three-year survival rate in elderly

patients with newly diagnosed Philadelphia

chromosome (Ph) negative ALL treated with

blinatumomab followed by POMP maintenance.

To evaluate in a preliminary manner (feasibility

study) the safety of dasatinib-steroid based induction

followed by blinatumomab treatment in combination

with dasatinib followed by dasatinib-based

maintenance in elderly patients with newly diagnosed

Ph-positive ALL, relapsed/refractory Ph-positive

ALL, and Ph-like DSMKF ALL (newly-diagnosed

relapsed or refractory).

To evaluate toxicities in these patient populations

treated with these regimens.

To estimate the rates of complete response (CR),

complete response with incomplete count recovery

(CRi), and disease-free survival in Ph-negative

patients.

To estimate disease-free and overall survival in Ph-

positive ALL and Ph-like DSMKF ALL.

To estimate in each cohort the rate of minimal

residual disease (MRD) negativity, and the time to

achieve MRD negativity (exploratory analysis).

To determine whether anti-idiotype antibodies

directed against blinatumomab develop with

blinatumomab treatment in this study.

Patient Population Patients must have a new morphologic diagnosis of

precursor B cell acute lymphoblastic leukemia (ALL)

(non-T cell) based on WHO criteria as defined in the

protocol. Patients with Burkitt's (L3) are not eligible

for this study. Patients with Ph-positive or Ph-like

ALL with dasatinib-sensitive mutations or kinase

fusions (DSMKF) may have relapsed or refractory

diagnoses. Patients must have a diagnosis of Ph-

negative ALL or Ph-positive ALL by cytogenetics,

FISH or polymerase chain reaction (PCR). If not

already known, BCR-ABL status (p190 or p210)

must be evaluated in Ph-positive patients by PCR. To

be registered under the Ph-like DSMKF criterion, the

patient must have a known or presumed activating

Ph-like signature and dasatinib-sensitive mutation or

kinase fusion as defined in the protocol. Patients must

have evidence of ALL in their marrow or peripheral

blood with at least 20% lymphoblasts (at least 5% for

relapsed/refractory patients) within 14 days prior to

registration. At registration, relapsed/refractory

patients must submit pathology and cytogenetics

reports from time of original diagnosis.

Immunophenotyping of the blood or marrow

lymphoblasts must be performed to determine lineage

within 14 days prior to registration. Patients with

only extramedullary disease in the absence of bone

marrow or blood involvement are not eligible.

Patients must not have testicular involvement.

Patients must not have received any prior

chemotherapy, radiation therapy, or other therapy for

the treatment of ALL (other than those noted below)

and must not be receiving any immunosuppressive

therapy. Patients must not have received any prior

investigational therapy within 28 days prior to

registration. Patients may have received the following

within any time prior to registration: low dose

chemotherapy, TKI therapy, steroids, hydroxyurea,

leukapheresis, intrathecal chemotherapy, or

vincristine. Patients must not have received any

monoclonal antibody therapy within 42 days of

registration.

Patients must be at least 65 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate hepatic, cardiac and renal function. Patients

must not have a history or presence of clinically

relevant CNS pathology and must have a lumbar

puncture to determine CNS involvement of ALL

within 14 days prior to registration. Patients must not

have systemic fungal, bacterial, viral, or other

infection that is not controlled. Patients must not have

Grade 2 or higher neuropathy (cranial, motor or

sensory) within 14 days prior to registration. Patients

known to be positive for HIV may be eligible,

providing they meet the criteria in the protocol.

Patients must not be candidates for allogeneic

hematopoietic stem cell transplant. Patients must not

have any known autoimmune disease. Ph-negative

patients must have PT/PTT/INR/fibrinogen and

neurologic assessment tests within 28 days prior to

registration. Ph-positive patients must not have active

pericardial effusion, ascites, or pleural effusion of

any grade.

Stratification/Descriptive Factors Patients are stratified by Registration Cohort: Ph-

negative vs Ph-positive/Ph-like DSMKF.

Accrual Goals This study will accrue up to 26 eligible Ph-negative

patients. An interim analysis will be performed

among the first 11 patients. If at least five complete

remissions (CR or CRi) are observed, then the study


S1318/I-II

will continue to full accrual. The study will continue

accruing while the remission data is being reviewed.

This study will initially accrue six eligible and

evaluable Ph-positive/Ph-like DSMKF patients. If the

regimen is considered safe, then the study will accrue

nine additional eligible Ph-positive/Ph-like DSMKF

patients.

Summary Statement The study was activated on January 12, 2015. The

Ph-positive/Ph-like DSMKF cohort was temporarily

closed to Step 1 accrual on April 15, 2017 to assess

the safety profile. During this closure, the FDA

placed a temporary clinical hold on this cohort on

September 29, 2017 while they reviewed a recent

protocol amendment. The hold was lifted on

December 1, 2017, but the cohort remains closed to

accrual while the study team and NCI discuss

whether to expand this cohort. A protocol revision

that added translational medicine (TM) objectives

and that proposed expanding the Ph-positive/Ph-like

DSMKF cohort to 20 evaluable patients was

submitted to CTEP on August 2, 2018. This

amendment was disapproved for reasons related to

the TM proposal and a re-submission is in progress.

The Ph-negative cohort permanently closed to

accrual on September 15, 2017 after reaching its

accrual goal.

Thirty-one patients have enrolled to the Ph-negative

cohort and 16 have enrolled to the Ph-positive/Ph-

like DSMKF cohort. Two patients in the Ph-negative

cohort were ineligible: one due to elevated alkaline

phosphatase and another due to a final diagnosis of

follicular lymphoma. One patient in the Ph-negative

cohort went off treatment to receive an alternate

therapy per physician decision.

Of the 45 patients evaluable for toxicities during

induction, one patient in the Ph-negative cohort died

of treatment-related respiratory failure along with

Grade 4 dyspnea. Two other patients in the Ph-

negative cohort experienced treatment-related non-

hematologic Grade 4 toxicities: lung infection and

fever (1 patient each). Two patients in the Ph-

positive/Ph-like DSMKF cohort experienced

treatment-related non-hematologic Grade 4 febrile

neutropenia, sepsis, and lung infection (1 patient

each).

There have been no Grade 4 or higher treatment-

related non-hematologic toxicities reported during

post-remission. Two patients on the Ph-negative

cohort experienced Grade 4 treatment-related non-

hematologic events during maintenance: sepsis (2

patients), hypertension (1 patient), and respiratory

failure (1 patient).



Institutions

Total

Reg Institutions

Total

Reg

City of Hope Med Ctr 4 New Mexico MU-NCORP 1

Cleveland Clinic OH 4 Rochester, Univ of 1

Irvine, U of CA 3 San Diego, U of CA 1

So Calif, U of 3 UF Cancer Center/Arkansas, U of 1

Michigan, U of 2 Wichita NCORP 1

Birmingham, U of AL 1 Yale University 1

Greenville NCORP 1 ALLIANCE 15

Heartland NCORP 1 ECOG-ACRIN 6

Loma Linda Univ 1 Total (17 Institutions) 47


S1318/I-II



Data as of February 8, 2019

TOTAL Induction: Ph-

Induction:

Ph+/Ph-like

NUMBER REGISTERED 47 31 16

INELIGIBLE 2 2 0

ELIGIBLE 45 29 16

RESPONSE ASSESSMENT

Determinable 43 28 15

Not Determinable 2 1 1


Evaluable 45 29 16




Induction: Ph-

(n=29)

Induction:

Ph+/Ph-like

(n=16)

AGE

Median 75.4 73.3

Minimum 66.3 48.1

Maximum 84.0 87.2

SEX

Males 22 76% 3 19%

Females 7 24% 13 81%

HISPANIC

Yes 2 7% 3 19%

No 27 93% 12 75%

Unknown 0 0% 1 6%

RACE

White 28 97% 12 75%

Asian 1 3% 2 13%

Unknown 0 0% 2 13%


S1318/I-II

Treatment Summary

Induction


TOTAL Induction: Ph-

Induction:

Ph+/Ph-like

NUMBER ON PROTOCOL TREATMENT 0 0 0

NUMBER OFF PROTOCOL TREATMENT REASON OFF TREATMENT

45 29 16

Treatment completed as planned 36 24 12

Adverse Event or side effects 3 1 2

Refusal unrelated to adverse event 1 1 0

Progression/relapse 1 1 0

Death 3 1 2

Other - not protocol specified 1 1 0

MAJOR PROTOCOL DEVIATIONS 0 0 0

LOST TO FOLLOW-UP 0 0 0

CONSENT WITHDRAWAL AFTER TREATMENT INITIATION

2 2 0


Induction





Induction: Ph-

(n=29)

Grade

Induction: Ph+/Ph-like

(n=16)

Grade


ALT increased 28 1 0 0 16 0 0 0

Confusion 28 1 0 0 16 0 0 0

Cytokine release syndrome 28 1 0 0 16 0 0 0

Dehydration 29 0 0 0 15 1 0 0

Diarrhea 28 1 0 0 15 1 0 0

Dysarthria 28 1 0 0 16 0 0 0

Dyspnea 26 2 1 0 15 1 0 0

Edema limbs 29 0 0 0 15 1 0 0

Fatigue 28 1 0 0 16 0 0 0

Febrile neutropenia 26 3 0 0 15 0 1 0

Fever 28 0 1 0 16 0 0 0

Generalized muscle weakness 29 0 0 0 15 1 0 0

Heart failure 29 0 0 0 15 1 0 0

Hematoma 29 0 0 0 15 1 0 0

Hyperglycemia 25 4 0 0 15 1 0 0

Hypertension 26 3 0 0 16 0 0 0

Hypocalcemia 28 1 0 0 16 0 0 0


S1318/I-II

Induction: Ph-

(n=29)

Grade

Induction: Ph+/Ph-like

(n=16)

Grade


Hyponatremia 29 0 0 0 15 1 0 0

Hypophosphatemia 28 1 0 0 16 0 0 0

Hypotension 28 1 0 0 16 0 0 0

Hypoxia 28 1 0 0 15 1 0 0

Infections/infestations-Other 28 1 0 0 15 1 0 0

Infusion related reaction 28 1 0 0 16 0 0 0

Lung infection 27 1 1 0 14 1 1 0

Nausea 29 0 0 0 15 1 0 0

Nervous sys disorders-Other 28 1 0 0 16 0 0 0

Pneumonitis 28 1 0 0 16 0 0 0

Respiratory failure 28 0 0 1 16 0 0 0

Sepsis 29 0 0 0 15 0 1 0

TTP 28 1 0 0 16 0 0 0

Urinary tract infection 29 0 0 0 15 1 0 0


EVENT

13 13 2 1 9 5 2 0


S1612/II-III

S1612 Phase II-III


A Randomized Phase II/III Trial of "Novel Therapeutics" Versus Azacitidine

in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML) or High-

Risk Myelodysplastic Syndrome (MDS), Age 60 or Older

LEAP: LEss-Intense AML Platform Trial

Participants:

SWOG, CTSU (Supported by CCTG and ECOG-

ACRIN)

Study Chairs:

L Michaelis, R Walter, S Assouline (CCTG), A Im

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

Date Activated:

12/22/2017

Date Closed*:

10/19/2018

*Temporary closure

SCHEMA

Objectives Phase II Component: To select, based on overall

survival, any or all of the "Novel Therapeutic"

regimens for further testing against azacitidine in

patients age 60 and older with newly diagnosed acute

myeloid leukemia (AML) or myelodysplastic

syndrome with excessive blasts-2 (MDS-EB-2).

Phase III Component: To compare overall survival of

the "Novel Therapeutic" regimens selected in the

R

E

G

I

S

T

R

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm A (control):

Azacitidine

Arm B:

Azacitidine + Nivolumab

Arm C:

Azacitidine + Midostaurin

Arm D*:

Decitabine/Cytarabine

*NOTE: Arm D will open to accrual when Arms B and C have met Phase II accrual and

are temporarily closed for Phase II analysis

FLT3 Testing


S1612/II-III

Phase II portion of the trial to azacitidine in these

patient populations.


of the regimens in these patient populations.

To estimate response rates, event-free survival, and

relapse-free survival for these regimens in these

patient populations.

Patient Population Patients must have morphologically confirmed,

previously untreated AML or MDS-EB-2. Patients

with acute promyelocytic leukemia, biphenotypic

leukemia, blastic transformation of chronic

myelogenous leukemia are not eligible. Patients must

have disease present in the blood or bone marrow;

patients with only extramedullary disease are not

eligible. Patients must not be known to have AML in

the CNS. Patients must be deemed, in the judgment

of the treating physician, to be ineligible for intensive

induction therapy or must have refused intensive

induction therapy.

Patients who have received prior therapy with

midostaurin, any anti-PD-1 or anti-PD-L1 therapy,

any DNA-methyltransferase inhibitor, or prior 7+3

therapy for MDS are not eligible. Patients who are

transfusion-dependent and patients receiving growth

factor support are eligible; patients must discontinue

growth factor support prior to initiation of protocol

therapy. Prior malignancy is allowed providing

concurrent therapy is not required; active hormonal

therapy is allowed.

Patients must be at least 60 years old and must be

able to swallow oral medications. Clinical evaluation

at baseline including hematologic, hepatic, renal,

cardiac, and coagulation parameters must be

completed per protocol. Women and men must be

willing to use contraception as outlined in the

protocol. Patients must not have active infection

(systemic bacterial, fungal, or viral infection) that is

not controlled. Patients must be eligible for at least

one of the currently enrolling investigational

treatment arms. Refer to the protocol for arm-specific

eligibility criteria.

Patients must have specimens submitted for FLT3

testing as outlined in the protocol for randomization

stratification. Pretreatment cytogenetics must be

performed on all patients as outlined in the protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by the

following factors: (1) Zubrod performance status: 0-1

vs 2-4; (2) FLT3-ITD status based on central

laboratory results: wild type FLT3 vs mutated FLT3-

ITD vs non-evaluable; and (3) baseline blast

percentage: MDS-EB-2 (< 20%) vs AML (20% or

higher).

Up to 100 eligible patients will be enrolled to each

arm for Phase II analysis. Up to 200 additional

eligible patients will be enrolled to each arm for

Phase III analysis. If all three experimental arms

complete full Phase III accrual, this study will enroll

approximately 1,500 eligible patients.

The Phase II interim analysis to evaluate for stopping

for futility will be performed when 52 events have

been observed. For arms carried forward for Phase III

testing, two additional interim analyses will be

performed when 50% and 75% of the expected

events have been observed (207 and 311 events,

respectively).

Summary Statement This trial was activated on December 22, 2017. On

October 19, 2018, the study team temporarily closed

all arms to accrual after observing unexpected

toxicities on the Aza + Nivo arm during the first two

cycles of therapy. The FDA placed a partial clinical

hold on this trial on October 25, 2018, mandating that

all patients discontinue nivolumab and that the Aza +

Nivo arm remain closed pending review of safety

information. The Aza and Aza + Mido arms were

allowed to re-open. A protocol revision was

submitted to CTEP on January 25, 2019 to re-open

the Aza and Aza + Mido arms of this study. The FDA

and study team continue to monitor and review safety

data for the Aza + Nivo arm.

As of October 19, 2018, 78 patients have been

randomized (26 per arm). Two randomized patients

did not have sufficiently high baseline blasts counts

and were therefore ineligible (one each on the Aza +

Nivo and Aza + Mido arms). Twelve patients went

off protocol treatment for reasons other than those

specified in the protocol, primarily due to treatment

futility, physician decision, or to receive different

therapy (11). One additional patient went off-

treatment because the patient did not wish to hold

study drug per protocol for a Grade 3 toxicity. One

patient each on the Aza and Aza + Mido arms

withdrew from protocol therapy prior to receiving

treatment. Another patient on the Aza + Mido arm

died prior to starting treatment. These three patients


S1612/II-III

are considered major protocol deviations and are not

analyzable for adverse events but will be analyzed for

other endpoints.

Of the 71 patients who have been evaluated for

adverse events, nine have experienced Grade 5 non-

hematologic toxicities related to treatment: three had

sepsis (2 Aza + Nivo, 1 Aza), three had respiratory

failure (2 Aza + Nivo, 1 Aza + Mido), and one each

had heart failure (Aza + Mido), lung infection (Aza +

Mido), and sudden death of indeterminate cause (Aza

+ Nivo - study drug could not be ruled out as cause of

death). One patient on the Aza + Nivo arm who died

of respiratory failure also had Grade 4 treatment-

related lung infection (coded as

Infections/infestations-Other). Nine other patients

have experienced Grade 4 treatment-related non-

hematologic adverse events (2 Aza, 5 Aza + Nivo, 2

Aza + Mido), including one patient with

hemophagocytic lymphohistiocytosis (coded as

Immune sys disorders-Other).


Randomization


Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 9 Arizona MC, U of 1

Heartland NCORP 6 Carle CC NCORP 1

H Lee Moffitt CC 3 Davis, U of CA 1

Montana NCORP 3 Georgia NCORP 1

New Mexico MU-NCORP 3 Loyola University 1

Rochester, Univ of 3 Southeast COR NCORP 1

Greenville NCORP 2 ALLIANCE 23

Michigan CRC NCORP 2 NRG 12

PCRC NCORP 2 ECOG-ACRIN 2

Wayne State Univ 2 Total (19 Institutions) 78



TOTAL Azacitidine

Azacitidine +

Nivolumab

Azacitidine +

Midostaurin

NUMBER REGISTERED 78 26 26 26

INELIGIBLE 2 0 1 1

ELIGIBLE 76 26 25 25

Analyzable, Pend. Elig. 8 4 3 1


Evaluable 71 24 24 23

Not Evaluable 3 1 0 2

Too Early 2 1 1 0


S1612/II-III



Azacitidine

(n=26)

Azacitidine +

Nivolumab

(n=25)

Azacitidine +

Midostaurin

(n=25)

AGE

Median 75.4 76.4 76.2

Minimum 61.9 66.4 65.7

Maximum 86.3 86.5 85.8

SEX

Males 15 58% 17 68% 16 64%

Females 11 42% 8 32% 9 36%

HISPANIC

Yes 0 0% 1 4% 1 4%

No 25 96% 23 92% 23 92%

Unknown 1 4% 1 4% 1 4%

RACE

White 23 88% 21 84% 21 84%

Black 2 8% 3 12% 2 8%

Asian 1 4% 0 0% 0 0%

Unknown 0 0% 1 4% 2 8%

BASELINE BLAST PERCENTAGE

<20% (MDS-EB-2) 8 31% 6 24% 6 24%

≥20% (AML) 18 69% 19 76% 19 76%

FLT3 - CENTRALLY REVIEWED

Wild type FLT3-ITD 25 96% 21 84% 22 88%

Mutated FLT3-ITD 1 4% 4 16% 3 12%

ZUBROD PERFORMANCE STATUS

0-1 21 81% 21 84% 20 80%

2-4 5 19% 4 16% 5 20%


S1612/II-III

Treatment Summary


TOTAL

NUMBER ON PROTOCOL TREATMENT 19

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

57

Treatment completed as planned 0

Adverse Event or side effects 6

Refusal unrelated to adverse event 6

Progression/relapse 8

Death 11

Other - not protocol specified 12

Reason under review 14

MAJOR PROTOCOL DEVIATIONS 3

LOST TO FOLLOW-UP 0

CONSENT WITHDRAWAL AFTER

TREATMENT INITIATION

0






Azacitidine

(n=24)

Grade


(n=24)

Grade


(n=23)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

ALT increased 24 0 0 0 23 1 0 0 23 0 0 0

AST increased 24 0 0 0 23 0 1 0 23 0 0 0

Acidosis 23 1 0 0 24 0 0 0 23 0 0 0

Acute kidney injury 24 0 0 0 23 1 0 0 23 0 0 0

Anorexia 24 0 0 0 24 0 0 0 22 1 0 0

Arthralgia 24 0 0 0 23 1 0 0 23 0 0 0

Atrial fibrillation 24 0 0 0 24 0 0 0 22 1 0 0

Back pain 24 0 0 0 24 0 0 0 22 1 0 0

Cardiac troponin I increased 23 1 0 0 24 0 0 0 23 0 0 0

Chest pain - cardiac 24 0 0 0 24 0 0 0 22 1 0 0

Constipation 24 0 0 0 23 1 0 0 23 0 0 0

Dry mouth 24 0 0 0 24 0 0 0 22 1 0 0

Dyspnea 24 0 0 0 24 0 0 0 22 1 0 0

ECG QT corrected int prolong 24 0 0 0 24 0 0 0 22 1 0 0

Ejection fraction decreased 24 0 0 0 23 1 0 0 23 0 0 0

Epistaxis 23 1 0 0 24 0 0 0 23 0 0 0

Fatigue 23 1 0 0 23 1 0 0 20 3 0 0

Febrile neutropenia 14 9 1 0 17 6 1 0 14 8 1 0

Fever 24 0 0 0 23 1 0 0 23 0 0 0

GI disorders-Other, specify 23 1 0 0 24 0 0 0 23 0 0 0

Generalized muscle weakness 24 0 0 0 23 1 0 0 22 1 0 0

Heart failure 23 1 0 0 23 0 1 0 21 1 0 1

Hyperglycemia 24 0 0 0 24 0 0 0 22 1 0 0


S1612/II-III

Azacitidine

(n=24)

Grade


(n=24)

Grade


(n=23)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Hypertension 24 0 0 0 24 0 0 0 22 1 0 0

Hypoalbuminemia 23 1 0 0 23 1 0 0 23 0 0 0

Hypokalemia 23 1 0 0 23 0 1 0 23 0 0 0

Hyponatremia 24 0 0 0 23 1 0 0 22 1 0 0

Hypophosphatemia 24 0 0 0 23 1 0 0 23 0 0 0

Hypotension 24 0 0 0 22 2 0 0 20 3 0 0

Hypoxia 23 0 1 0 23 1 0 0 23 0 0 0

INR increased 24 0 0 0 24 0 0 0 22 1 0 0

Immune sys disorders-Other 24 0 0 0 23 0 1 0 23 0 0 0

Infections/infestations-Other 24 0 0 0 22 1 1 0 20 3 0 0

Joint infection 24 0 0 0 24 0 0 0 22 1 0 0

Lung infection 22 1 1 0 18 4 2 0 19 3 0 1

Mucositis oral 24 0 0 0 24 0 0 0 21 2 0 0

Pneumonitis 24 0 0 0 23 0 1 0 23 0 0 0

Pruritus 23 1 0 0 24 0 0 0 23 0 0 0

Pulmonary edema 24 0 0 0 24 0 0 0 22 0 1 0

Rash maculo-papular 23 1 0 0 24 0 0 0 23 0 0 0

Respiratory failure 24 0 0 0 22 0 0 2 22 0 0 1

Sepsis 22 0 1 1 20 0 2 2 22 0 1 0

Skin infection 24 0 0 0 23 1 0 0 23 0 0 0

Sudden death NOS 24 0 0 0 23 0 0 1 23 0 0 0

Supraventricular tachycardia 23 1 0 0 24 0 0 0 23 0 0 0

Typhlitis 24 0 0 0 24 0 0 0 22 1 0 0


EVENT

11 10 2 1 9 5 5 5 8 10 2 3


S1712/II

S1712 Phase II


A Randomized Phase II Study of Ruxolitinib (NSC-752295) in Combination

with BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

(CML) Patients with Molecular Evidence of Disease

Participants:

SWOG, CTSU

Study Chairs:

K Sweet, J Radich

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

07/20/2018

SCHEMA

Objectives To compare the rate of molecular response 4.5

(MR4.5) after 12 months of combination therapy

with ruxolitinib plus a TKI (dasatinib or nilotinib)

versus a TKI alone, based on local PCR testing to

measure BCR-ABL transcripts in chronic phase CML

patients with molecular evidence of disease.


of each regimen in this patient population.

To estimate progression-free survival and overall

survival of each regimen in this patient population.

Patient Population Patients must have a diagnosis of chronic phase

chronic myeloid leukemia (CML) without any history

of progression to accelerated or blast phase CML as

defined in the protocol. Patients must have detectable

BCR-ABL transcripts measured by RT-PCR at a

CLIA-approved laboratory as outlined in the

protocol.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm 1:

Single-agent TKI

Arm 2:

Single-agent TKI

+Ruxolitinib


S1712/II

Patients must be receiving treatment with dasatinib or

nilotinib as first- or second-line therapy for a

minimum of six months prior to registration and must

be expected to remain on the same TKI for the next

12 months. If receiving second-line therapy, the

reason for stopping first-line treatment must not have

been resistance to treatment or failure to achieve an

adequate response. Patients must not have received

more than two TKIs for treatment of CML.

Hydroxyurea prior to initiation of TKI is allowed.

Patients must have been receiving TKI treatment for

CML for at least one year and for no more than 10

years prior to randomization. Prior malignancy is

allowed providing it does not require concurrent

therapy; active hormonal therapy is allowed.

Patients must have adequate hematologic, hepatic,

renal, and cardiac function. Patients known to be

HIV+ are allowed provided they have undetectable

HIV viral loads.

Patients must be offered participation in specimen

banking for future research. With patient consent,

specimens must be submitted as outlined in the

protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by the

following factors: (1) time on any TKI therapy prior

to randomization: ≥ 1 and < 4 years vs ≥ 4 and ≤ 10

years; and (2) current TKI: dasatinib vs nilotinib.

Accrual Goals The accrual goal is 84 patients to achieve 74 eligible

patients (37 per arm).

One interim analysis is planned at the time when 12-

month MR4.5 data are available from 19 patients on

each arm.

Summary Statement This study activated on July 20, 2018. As of

December 31, 2018, two patients have been

randomized (one to each arm), both of whom are

eligible. Both patients are on protocol treatment and

neither has experienced any treatment-related adverse

events.



Institutions Total Reg

Heartland NCORP 2

Total (1 Institutions) 2

ECOG-ACRIN Cancer Research Group E1910 Study Progress and Safety Report Fall 2018

Page 1

E1910 A PHASE III RANDOMIZED TRIAL OF BLINATUMOMAB FOR NEWLY DIAGNOSED BCR-ABL NEGATIVE B ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Mark Litzow Statistician Dr. Zhuoxin Sun Data Specialist Henry Baptista Phase of Study III Type of Study Therapeutic Committee Leukemia Accrual Objective 488 Patients Participating Groups ECOG-ACRIN, CTSU DCP Treatment Credit 1.0 NSC# 740, 3590, 10023, 14575, 26271, 34521, 63878,

67574, 141540, 624239, 697732, 765986 Clinicaltrials.gov Study ID NCT02003222 Study Status Open to Accrual Date Proposed June 26, 2012 Date Activated December 17, 2013 Schema


Page 2


Page 3

Purpose of Study 1) To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with BCR-ABL-negative B cell precursor ALL who are MRD negative after induction and intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of residual blasts. 2) To compare the relapse-free survival (RFS) of blinatumomab in conjunction with chemotherapy to chemotherapy alone in MRD negative patients after induction and intensification chemotherapy. 3) To compare the OS and RFS of those patients who are MRD+ at step 3 randomization/ registration and then convert to MRD- after 2 cycles of blinatumomab to those patients who are MRD- at randomization and remain MRD- after 2 cycles of blinatumomab or consolidation chemotherapy. 4) To assess the toxicities of blinatumomab in this patient population. 5) To assess the toxicities of the modified E2993 chemotherapy regimen in this patient population. 6) To describe the outcome of patients who proceed to allogeneic blood or marrow transplant after treatment with or without blinatumomab. 7) To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage ALL, and to compare the OS (and RFS) of patients with BCR-ABL-like phenotype with those without BCR-ABL-like phenotype. 8) To evaluate the incidence of anti-blinatumomab antibody formation. Study Population Newly diagnosed, previously untreated BCR-ABL negative B cell precursor acute lymphoblastic leukemia patients aged 30-70.


Page 4

Summary of Study Design The primary objective of the study will be to compare the OS in patients who received blinatumomab in conjunction with chemotherapy to that of patients who received chemotherapy alone in MRD- patients. OS is defined as the time between randomization and death from any cause. Patients last known to be alive at the time of an analysis will be censored. We plan to enter a total of 488 BCR/ABL-negative B cell precursor ALL patients aged 30-70 in this study. We assume that a total of 190 (39% of the 488) patients will be MRD- and be randomized to receive either blinatumomab or no blinatumomab. Based on E2993, we assume the survival function of this ALL patient population can be described by a cure rate model. For MRD- patients, we assume a 35% long-term cure rate and 13-month median OS in the non-cured group in the control arm. Adjusted for sequential monitoring, with 190 MRD- patients, the study will have 80% power to detect 45% reduction in hazard rate in the blinatumomab arm relative to the no blinatumomab arm, using one-sided log rank test at the significance level of 0.025 and assuming 2 years of follow-up, which is equivalent to detecting an improvement in the 3-year OS rate from 45% to 64%. The number of events needed is 94. Progress to Date This study was activated on December 17, 2013. As of July 17, 2018, 342 patients have been accrued. Accrual status and accrual by group are summarized in Tables 1a, 1b and 1c. Expected and actual cumulative accrual are shown in Figure 1. Patient status as of July 17, 2018 is summarized in Table 2. Demographic data are shown in Tables 3a, 3b, 3c and 3d. Record status is shown in Table 4. The distribution of the reasons for discontinuation of protocol treatment is given in Table 5 by step. Treatment-related toxicity data are available on 297 patients and are summarized in Table 6 by step, treatment arm and cycle. Table 7 summarizes lethal adverse events (regardless of treatment relation). Table 8 summarizes incidences of second primary cancer. Outcome data are not included in this report, but will be presented to the Data Safety Monitoring Committee when appropriate.


Page 5

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Step 2 Step 3 Step 4 Beaumont NCORP 0 0 0 0 Beth Israel Deaconess Medical Center 2 2 1 0 Cancer Research Consortium of West Michigan NCORP 1 1 1 0 Dayton NCORP 1 1 0 0 Emory University/Winship Cancer Institute 1 1 1 0 Froedtert and the Medical College of Wisconsin 16 10 8 3 Geisinger Cancer Institute NCORP 0 0 0 0 Georgia NCORP 7 2 2 0 Gulf South MU NCORP 1 0 0 0 Heartland Cancer Research NCORP 1 0 0 0 Johns Hopkins Univ/Sidney Kimmel Cancer Center 27 22 20 7 Loyola University Medical Center 1 1 1 0 Mayo Clinic 9 5 2 0 Montana Cancer Consortium NCORP 1 0 0 0 NorthShore Univ HealthSystem-Evanston Hospital 2 1 1 0 Northwestern University 16 8 7 2 Ochsner NCORP 2 1 1 1 Pacific Cancer Research Consortium NCORP 0 1 0 1 Penn State Milton S Hershey Medical Center 1 0 0 0 Rutgers Cancer Institute of New Jersey 5 3 3 0 Stanford Cancer Institute Palo Alto 1 0 0 0 Stony Brook University Medical Center 0 0 0 0 Thomas Jefferson University Hospital 2 0 0 0 UT Southwestern/Simmons Cancer Center-Dallas 1 0 0 0 University of Alabama at Birmingham Cancer Center 1 1 1 1 University of Pennsylvania/Abramson Cancer Center 18 12 8 4 University of Wisconsin Hospital and Clinics 8 5 5 2 VCU Massey Cancer Center MU NCORP 12 8 5 0 Washington University School of Medicine 4 1 1 0 Wichita NCORP 4 2 2 1 Wisconsin NCORP 1 0 0 0 Total 146 88 70 22

Table 1b. Accrual by Group

Step 1 Step 2 Step 3 Step 4

ECOG-ACRIN 146 88 70 22 CCTG 4 0 0 0 SWOG 89 57 43 19 ALLIANCE 90 54 45 13 NRG 13 10 9 2 Total 342 209 167 56


Page 6

Table 1c. Projected Accrual

Step 1 Step 2 Step 3 Step 4 Accrual goal 488 Planned accrual rate 72/yr Accrual to date 342 209 167 56 Annual accrual rate

Overall 75/yr 46/yr 36/yr 12/yr Last 6 months 108/yr 82/yr 60/yr 24/yr

Projected date of closure November 2019


Page 7

Table 2. Patient Status as of July 17, 2018

Step 1 Step 2 Step 3 Step 4 Cases Entered 342 209 167 56 Ineligible 6 5 3 0 Never Started Assigned Therapy 3 0 2 0

Reason for ineligibility Step 1:

Patient was BCR/ABL+ (19004, 19063, 19142, 19193, 19259). Bone Marrow pathology report was not done (19155).

Reason for not starting assigned therapy Step 1: Patient withdrawal/refusal (19066); patient ineligible (19155, 19193).

Reason for ineligibility Step 2:

CR/CRi not confirmed (19037, 19053, 19139, 19194, 19218).

Reason for ineligibility Step 3: Baseline labs (bilirubin, creatinine, anc, blasts, platelets) not done before randomization (19040); Serum Creatinine and Bilirubin were not obtained within 48 of step 3 registration in order to confirm eligibility (19051, 19053).

Reason for not starting assigned therapy Step 3:

Patient withdrawal/refusal (19093); Disease progression (19044).


Page 8

Table 3a. Demographics --Step 1

Variable Level Arm A

(n=342) Sex Male 177 (51.8)

Female 165 (48.2) Race White 272 (89.8)

African-American 17 (5.6) Asian 7 (2.3) Native Hawaiian 1 (0.3) Native American 4 (1.3) Multirace 2 (0.7) Unknown/Unreported 39

Ethnicity Hispanic 48 (15.0) Non-Hispanic 273 (85.0) Unknown/Missing 21

Age Median 51 Minimum 30 Maximum 70

Table 3b. Demographics --Step 2

Variable Level Arm B

(n=209) Sex Male 107 (51.2)

Female 102 (48.8) Race White 169 (89.9)

African-American 11 (5.9) Asian 4 (2.1) Native Hawaiian 1 (0.5) Native American 2 (1.1) Multirace 1 (0.5) Unknown/Unreported 21




Page 9

Table 3c. Demographics --Step 3

Variable Level Arm C (n=84)

Arm D (n=83)

Total (n=167)

Sex Male 40 (47.6) 45 (54.2) 85 (50.9) Female 44 (52.4) 38 (45.8) 82 (49.1)

Race White 67 (87.0) 69 (95.8) 136 (91.3) African-American 8 (10.4) 3 (4.2) 11 (7.4) Native Hawaiian 1 (1.3) 0 (0.0) 1 (0.7) Native American 1 (1.3) 0 (0.0) 1 (0.7) Unknown/Unreported 7 11 18

Ethnicity Hispanic 12 (14.6) 12 (15.6) 24 (15.1) Non-Hispanic 70 (85.4) 65 (84.4) 135 (84.9) Unknown/Missing 2 6 8

Age Median 52 52 52 Minimum 31 30 30 Maximum 68 70 70

Table 3d. Demographics --Step 4

Variable Level Arm E (n=56)

Sex Male 26 (46.4) Female 30 (53.6)

Race White 45 (95.7) African-American 1 (2.1) Native Hawaiian 1 (2.1) Unknown/Unreported 9




Page 10

Table 4. Record Status

Form Name Forms

Due Forms

Received % Demography 338 338 100 Patient Characteristics 730 723 99.04 Treatment Agent: 6 Mercaptopurine 517 509 98.45 Treatment Agent: Blinatumomab 204 203 99.51 Treatment Agent: Cyclophosphamide (1d) 64 64 100 Treatment Agent: Cyclophosphamide (2d) 265 261 98.49 Treatment Agent: Cytarabine (16d) 266 261 98.12 Treatment Agent: Cytarabine (1d) 313 311 99.36 Treatment Agent: Cytarabine (5d) 232 232 100 Treatment Agent: Cytarabine (8d) 64 64 100 Treatment Agent: Daunorubicin (4d) 375 373 99.47 Treatment Agent: Dexamethasone 374 371 99.2 Treatment Agent: Etoposide (5d) 232 232 100 Treatment Agent: Leucovorin 191 189 98.95 Treatment Agent: Methotrexate (13d) 190 188 98.95 Treatment Agent: Methotrexate (1d) 609 606 99.51 Treatment Agent: Methotrexate (2d) 192 190 98.96 Treatment Agent: Methotrexate (4d) 267 263 98.5 Treatment Agent: Methotrexate IT (1d) 127 127 100 Treatment Agent: Pegaspargase 867 857 98.85 Treatment Agent: Prednisone 194 193 99.48 Treatment Agent: Rituximab (1d) 33 33 100 Treatment Agent: Rituximab (2d) 117 112 95.73 Treatment Agent: Vincristine (1d) 198 198 100 Treatment Agent: Vincristine (4d) 374 372 99.47 Treatment: Substitution Agent Form 1 1 100 Adverse Event Form 1463 1393 95.22 Follow-Up Hematology/Chemistry 13608 13576 99.76 Late Adverse Event Form 27 27 100 Other Adverse Event Form 751 748 99.6 Disease Follow-up Status 2015 1994 98.96 Off Treatment 64 63 98.44 Off-Treatment with Intent to Reg Next St 569 560 98.42


Page 11

Table 5a. Reasons Off Treatment - Step 1

For Patients Not Registered To Subsequent Steps (Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 8 8.6 Alternative therapy 6 6.5 Death on study 8 8.6 Disease progression- relapse during active treatment 20 21.5 Other 28 30.1 Patient off-treatment for other complicating disease 2 2.2 Patient withdrawal/refusal after beginning protocol therapy 10 10.8 Treatment completed per protocol criteria 11 11.8 Total off treatment 93 100.0

Table 5b. Reasons Off Treatment - Step 2 For Patients Not Registered To Subsequent Steps (Includes all patients who started treatment and


Reasons N % Adverse event/side effects/complications 1 2.9 Alternative therapy 1 2.9 Disease progression- relapse during active treatment 11 32.4 Other 5 14.7 Patient withdrawal/refusal after beginning protocol therapy 2 5.9 Treatment completed per protocol criteria 14 41.2 Total off treatment 34 100.0

Table 5c. Reasons Off Treatment - Step 3 For Patients Not Registered To Subsequent Steps (Includes all patients who started treatment and


Reasons N % Adverse event/side effects/complications 4 5.6 Alternative therapy 6 8.3 Death on study 3 4.2 Disease progression- relapse during active treatment 14 19.4 Other 3 4.2 Patient withdrawal/refusal after beginning protocol therapy 3 4.2 Treatment completed per protocol criteria 39 54.2 Total off treatment 72 100.0


Page 12

Table 5d. Reasons Off Treatment - Step 4 (Includes all patients who started treatment and


Reasons N % Adverse event/side effects/complications 1 3.6 Alternative therapy 1 3.6 Death on study 1 3.6 Disease progression- relapse during active treatment 6 21.4 Other 3 10.7 Patient withdrawal/refusal after beginning protocol therapy 3 10.7 Treatment completed per protocol criteria 12 42.9 Total off treatment 27 96.4


Page 13

Table 6. Toxicity Incidence (Treatment-Related) Step 1 (Arm A)

Toxicity Type

Treatment Arm A (n=297)

Grade 3 4 5

(n) (n) (n) Anemia 144 21 - Blood and lymphatic system disorders - Other, specify 1 3 - Disseminated intravascular coagulation 1 - - Febrile neutropenia 65 3 - Cardiac disorders - Other, specify - 1 - Chest pain - cardiac 1 - - Myocardial infarction - - 1 Pericarditis 1 - - Sinus bradycardia 1 - - Sinus tachycardia 1 - - Fatigue 24 - - Fever 2 - - General disorders and administration site conditions - Other, specify 1 - - Pain 1 - - Infusion related reaction 1 - - Rash maculo-papular 1 - - Urticaria 1 - - Abdominal pain 5 - - Constipation 2 - - Diarrhea 5 - - Gastrointestinal disorders - Other, specify 2 - - Mucositis oral 4 - - Nausea 12 - - Pancreatitis 6 - - Rectal pain 2 - - Small intestinal obstruction - 1 - Vomiting 11 - - Hepatic failure - 2 - Hepatobiliary disorders - Other, specify - 1 - Allergic reaction 1 - - Anaphylaxis 1 - - Catheter related infection 6 - - Eye infection 1 - - Infections and infestations - Other, specify 9 1 - Sepsis - 11 1 Sinusitis 3 - - Skin infection 4 - - Urinary tract infection 5 - - Pancreas infection 1 - -


Page 14

Toxicity Type


Grade 3 4 5

(n) (n) (n) Abdominal infection 1 - - Bone infection 1 - - Lung infection 6 1 - Activated partial thromboplastin time prolonged 2 - - Alanine aminotransferase increased 26 4 - Alkaline phosphatase increased 9 - - Aspartate aminotransferase increased 16 1 - Blood bilirubin increased 20 9 - Cholesterol high - 1 - Fibrinogen decreased 5 5 - Investigations - Other, specify 1 1 - Lipase increased 1 1 - Lymphocyte count decreased 16 58 - Lymphocyte count increased 1 - - Neutrophil count decreased 9 227 - Platelet count decreased 23 195 - Weight loss 1 - - White blood cell decreased 2 148 - GGT increased 1 1 - Anorexia 6 - - Dehydration 5 - - Hyperglycemia 22 1 - Hyperkalemia 2 - - Hypertriglyceridemia 1 12 - Hyperuricemia - 1 - Hypoalbuminemia 5 - - Hypocalcemia 2 - - Hyponatremia 15 - - Hypophosphatemia 5 - - Tumor lysis syndrome 17 - - Glucose intolerance 3 - - Arthralgia 2 - - Back pain 1 - - Generalized muscle weakness 4 - - Muscle weakness lower limb 1 - - Cerebrospinal fluid leakage 1 - - Cognitive disturbance 1 - - Dizziness 2 - - Encephalopathy 2 1 - Headache 17 - - Intracranial hemorrhage 1 - - Paresthesia 1 - -


Page 15

Toxicity Type


Grade 3 4 5

(n) (n) (n) Seizure 1 - - Somnolence 1 - - Stroke 1 1 - Syncope 3 - - Vasovagal reaction 2 - - Retinopathy 1 - - Confusion 2 - - Delirium 1 - - Insomnia 1 - - Personality change 1 - - Restlessness 1 - - Adult respiratory distress syndrome - - 1 Dyspnea 3 - - Epistaxis 2 - - Hiccups 1 - - Hypoxia 2 - - Pneumonitis 2 - - Respiratory, thoracic and mediastinal disorders - Other, specify 1 - - Sore throat 1 - - Wheezing 1 - - Bronchopulmonary hemorrhage - 1 - Acute kidney injury 1 1 - Hematoma 1 - - Hypertension 13 - - Hypotension 5 1 - Thromboembolic event 6 4 - WORST DEGREE (NON-HEMATOLOGIC) 135 51 3


Page 16

Step 2 (Arm B)

Toxicity Type

Treatment Arm B (n=153)

Grade 3 4 5

(n) (n) (n) Anemia 30 1 - Febrile neutropenia 1 - - Fatigue 4 - - Hyperhidrosis 1 - - Abdominal pain 2 - - Diarrhea 3 - - Gastrointestinal disorders - Other, specify 1 - - Nausea 2 - - Pancreatitis 1 - - Anaphylaxis - 1 - Catheter related infection 2 - - Sepsis - 1 - Skin infection 1 - - Urinary tract infection 1 - - Activated partial thromboplastin time prolonged 1 - - Alanine aminotransferase increased 10 - - Alkaline phosphatase increased 3 - - Aspartate aminotransferase increased 8 - - Blood bilirubin increased 3 1 - Creatinine increased 1 - - Fibrinogen decreased 1 - - Investigations - Other, specify 1 - - Lipase increased 3 1 - Lymphocyte count decreased 15 10 - Neutrophil count decreased 27 20 - Platelet count decreased 7 10 - Weight loss 1 - - White blood cell decreased 9 4 - Alkalosis 1 - - Dehydration 1 - - Hyperglycemia 6 2 - Hypertriglyceridemia - 2 - Hypocalcemia 1 - - Hypokalemia 2 - - Hyponatremia 1 - - Hypophosphatemia 1 - - Tumor lysis syndrome 1 - - Glucose intolerance 1 - - Generalized muscle weakness 1 - - Headache 1 - - Hypertension 3 - - Hypotension 1 - - Thromboembolic event 1 - - WORST DEGREE (NON-HEMATOLOGIC) 39 8 -


Page 17

Step 3 Arm C

Toxicity Type

Treatment Arm C (n=69)

Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (

n)

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) Ear pain 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Anemia 5 - - - - - 5 - - 4 - - 14 - - 10 - - 2 - - 5 - - 1 - - 15 - - Blood and lymphatic system disorders - Other, specify

- 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Febrile neutropenia - - - 1 - - 1 - - 3 2 - 2 - - 4 - - 1 - - 2 - - - - - 9 2 - Chest pain - cardiac - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Sinus tachycardia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Fatigue - - - 1 - - 1 - - - - - - - - - - - - - - 1 - - - - - 1 - - Fever - - - - - - - - - - - - - - - 1 - - - - - 1 - - - - - 2 - - Abdominal pain - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Nausea - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Vomiting - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - Hepatobiliary disorders - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Cytokine release syndrome 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Appendicitis perforated - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Catheter related infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - - Device related infection - - - - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - - Infections and infestations - Other, specify 2 - - - - - 2 - - - - - - - - - - - 1 - - - - - - - - 1 - - Sepsis - - - - - - - - - - 3 - - - - - - - - - 1 - 1 - - - - - 4 1 Sinusitis - - - 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - - Urinary tract infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - - Activated partial thromboplastin time prolonged - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Alanine aminotransferase increased 1 1 - - - - 1 1 - 1 - - 1 - - - - - - 1 - - - - - - - 1 1 - Alkaline phosphatase increased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Aspartate aminotransferase increased 1 1 - - - - 1 1 - - - - 1 - - - - - - 1 - - - - - - - 1 1 - Cholesterol high - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - Fibrinogen decreased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Lymphocyte count decreased 2 7 - - 2 - 2 8 - 2 1 - 2 1 - 3 1 - 2 1 - 1 - - 2 - - 3 4 - Neutrophil count decreased 10 2 - 4 3 - 11 5 - - 2

7 - 2 19 - 3 24 - 3 2 - - 22 - 2 1 - 1 32 -

Platelet count decreased 1 2 - - 1 - 1 3 - 4 16

- 4 12 - 3 22 - - 1 - 1 15 - - - - 4 27 - Weight gain - - - - - - - - - - - - - - - - - - - - - - - - 1 - - 1 - -


Page 18

Toxicity Type

Treatment Arm C (n=69)

Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (

n)

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) White blood cell decreased - 1 - 1 - - 1 1 - 3 7 - 1 3 - 2 7 - - 2 - - 3 - - - - 3 13 - Dehydration 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hyperglycemia 1 - - - - - 1 - - 1 1 - 1 - - 4 - - - - - - - - 1 - - 3 1 - Hypertriglyceridemia - - - - - - - - - - 1 - - 2 - - 2 - 1 - - 1 - - - - - - 3 - Hypocalcemia - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Hyponatremia 1 - - - - - 1 - - 1 - - - - - 1 - - - - - - - - - - - 1 - - Hypophosphatemia - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Avascular necrosis 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Bone pain - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - Cognitive disturbance 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Concentration impairment 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Depressed level of consciousness 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Dysarthria 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - - Dysphasia 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - - Encephalopathy 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Headache - - - - - - - - - 1 - - 1 - - 1 - - - - - - - - 1 - - 4 - - Intracranial hemorrhage - - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - Nervous system disorders - Other, specify - - - - - - - - - - - - - - - - - - 1 - - - - - - - - 1 - - Seizure 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Syncope - - - - - - - - - 1 - - - - - 1 - - - - - 1 - - - - - 3 - - Tremor 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Confusion - - - - - - - - - - - - - - - - - - 1 - - - - - - - - 1 - - Epistaxis - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Capillary leak syndrome 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hypertension - 1 - - - - - 1 - - - - - - - 1 - - - - - - - - - - - 1 - - Hypotension - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Thromboembolic event - - - - - - - - - 1 - - 1 - - 1 - - 1 - - 1 - - 1 - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 12 2 1 4 - - 15 2 1 6 6 - 7 2 - 12 2 - 4 - 1 4 1 - 4 - - 17 7 1


Page 19

Step 3 Arm D

Toxicity Type

Treatment Arm D (n=61)

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycles

1-4 Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Toxicity Type 10 1 - 8 1 - 8 - - 2 1 - 22 2 - Anemia

Febrile neutropenia 6 1 - 2 - - 2 - - 2 - - 9 1 - Fatigue 3 - - - - - - - - - - - 3 - - General disorders and administration site conditions - Other, specify 1 - - - - - - - - - - - 1 - - Nausea 1 - - - - - - - - - - - 1 - - Vomiting 3 - - - - - - - - - - - 3 - - Allergic reaction 1 - - - - - - - - - - - 1 - - Catheter related infection 2 1 - - 1 - 1 - - - - - 3 1 - Infections and infestations - Other, specify 1 - - - - - - - - - - - 1 - - Lung infection - 1 - - - - - - - - - - - 1 - Sepsis - 3 - - 1 - - - - - - - - 3 - Sinusitis - - - - - - 1 - - - - - 1 - - Urinary tract infection - - - - - - 1 - - - - - 1 - - Alanine aminotransferase increased 1 - - - - - 2 - - - - - 3 - - Alkaline phosphatase increased 1 - - - - - - - - - - - 1 - - Lymphocyte count decreased 3 3 - 1 3 - 1 6 - 3 1 - 4 8 - Neutrophil count decreased 4 38 - 1 21 - 2 13 - 2 8 - 3 42 - Platelet count decreased 8 20 - 3 12 - 2 12 - - 4 - 8 29 - White blood cell decreased 2 15 - 1 5 - 2 6 - 1 4 - 1 21 - Hyperglycemia - - - - - - 2 1 - - - - 2 1 - Hypertriglyceridemia - 1 - - - - - - - - - - - 1 - Hyponatremia 1 - - - - - - - - - - - 1 - - Hypophosphatemia 2 - - - - - 1 - - - - - 2 - - Iron overload 1 - - 1 - - - - - - - - 1 - - Headache 2 - - 3 - - 2 - - 1 - - 5 - - Peripheral sensory neuropathy 1 - - 1 - - - - - - - - 1 - - Depression 1 - - - - - - - - - - - 1 - - Pneumonitis 1 - - - - - - - - - - - 1 - - Hypertension 1 - - - - - - - - - - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 10 5 - 6 1 - 8 1 - 3 - - 17 6 -


Page 20

Step 3 Transplant

Toxicity Type

Treatment Arm C (n=12) D (n=14)

Grade Grade 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) Anemia 3 - - 5 - - Febrile neutropenia 2 1 - 5 - - Atrial fibrillation 1 - - - - - Chills - - - 1 - - Fatigue 1 - - 1 - - Pain - - - 1 - - Dry skin - - - 1 - - Rash acneiform 1 - - - - - Anal mucositis - - - 1 - - Colitis 2 - - - - - Diarrhea 2 - - 1 - - Dry mouth - - - 1 - - Dysphagia - - - 1 - - Esophagitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral 2 - - 3 1 - Nausea 1 - - 1 - - Oral pain - - - 1 - - Typhlitis - - - 1 - - Infections and infestations - Other, specify 1 - - - - - Lung infection 1 - - 1 - - Lymphocyte count decreased - 3 - - 6 - Neutrophil count decreased - 8 - - 8 - Platelet count decreased 1 7 - - 8 - White blood cell decreased - 7 - - 6 - Anorexia 1 - - 3 - - Hyperglycemia 1 - - - - - Hypokalemia 1 - - - - - Iron overload - - - 1 - - Back pain - - - 1 - - Trismus - - - 1 - - Dyspnea - - - 1 - - Epistaxis - - - 1 - - Pulmonary edema - - - 1 - - Sore throat - - - 1 - - Hematuria - - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 4 1 - 6 1 -


Page 21

Step 4 Maintenance

Toxicity Type

Treatment Arm C (n=23) D (n=21)

Grade Grade 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) Anemia 3 - - 1 - - Febrile neutropenia 2 - - - - - Fatigue 1 - - - - - Mucositis oral 2 - - 1 - - Nausea 1 - - - - - Vomiting 1 - - - - - Infections and infestations - Other, specify 1 - - - - - Upper respiratory infection 1 - - - - - Lung infection 1 - - - - - Alanine aminotransferase increased 3 - - 4 - - Aspartate aminotransferase increased 1 - - 2 - - Blood bilirubin increased 1 - - 2 1 - Investigations - Other, specify 1 - - - - - Lymphocyte count decreased - 2 - 3 1 - Neutrophil count decreased - 11 - 2 5 - Platelet count decreased 3 2 - 2 3 - White blood cell decreased 1 2 - - 3 - Dehydration 1 - - - - - Hyperglycemia - - - 1 - - Hyponatremia 1 - - - - - Back pain - - - 1 - - Avascular necrosis 1 - - - - - Headache - - - 1 - - Peripheral sensory neuropathy - - - 1 - - Treatment related secondary malignancy - - 1 - - - Hypertension - - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 8 - 1 10 1 -


Page 22

Table 7. Lethal Adverse Events

Case Arm Description of Event 19001 A Death NOS 19126 A Intracranial hemorrhage 19215 A Sudden death NOS 19220 A Febrile neutropenia 19243 A Sepsis 19299 A Sepsis 19305 A Infections and infestations - Other 19345 A Adult respiratory distress syndrome 19378 A Hepatic failure 19452 A Sepsis 19456 A Myocardial infarction 19119 C Intracranial hemorrhage 19327 C Sepsis 19088 D Cardiac arrest 19047 E Cardiac arrest

Table 8. Second Primary Cancers (By arm during which event was reported)

Site Arm A Arm E

Acute Non-Lymphocytic Leukemia - ANLL, AML 1 - Leukemia, Type Not Specified - 1 Non-Small Cell Lung 1 - Pancreas 1 -

leukemia committee - swog 2019/rosbook... · 2019. 3. 20. · leukemia in their peripheral blood or...

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