Protocol 9090-08 Review

A Randomized, Phase IIB/III Study of Ganetespib (STA-9090) in Combination with Docetaxel Vs Docetaxel Alone in Subjects

with Stage IIIb/IV NSCLC

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Why Docetaxel? Why 2L NSCLC?

• Strong scientific rationale

– Complementary effects on cell cycle, microtubules

– Inhibition of taxane resistance mechanisms by ganetespib

– Ganetespib effects on tumor microenvironment

• Encouraging clinical rationale– Ganetespib and docetaxel are both clinically active in NSCLC– Toxicities are non-overlapping– Combination well-tolerated

• Very attractive, growing commercial opportunity– Increasing usage of docetaxel in 2L

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Phase 2, multi-center, randomized, open label study

240 patients to be enrolled in stage 1

Approximately ~55 centers in USA, Canada and EU 10 in North America 45 in Western EU, Central EU and Eastern EU

FCI: May 2011

Expect all centers activated by September

Recruitment Period: 11 months (May 11 to March 2012)

Treatment and survival F-U 9 months (Apr12-Dec12)

Stage 1 (Phase 2b) Study Overview

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D 75mg/m2 q3w + G 150 mg/m2 d1/15

RANDOMIZE

1:1

PFSOS

D 75mg/m2 q3w

Stage 1N = 240 patients

PFS endpoint

Stage 2N 500 patients

OS endpoint (TBD)• Same sites • Opportunity for patient enrichment

(population, biomarkers)• Regulatory advice

Phase 2b/3 NSCLC Study Design

Stage IIIB/IV NSCLC2nd line

Documented DP

Stratification PS, time since initial dx, LDH, histology

Outline of Review

Objective

Key eligibility criteria

Dosing

Assessments

QoL

RECIST

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Main Objectives

Primary

– Progression free survival (PFS)

– Overall Survival (OS) – in subjects with high baseline serum levels of total LDH

Secondary

– ORR, clinical benefit rate (CBR), mean tumor size change, 1-year OS, and OS

– Safety

– PK

– QOL: EORTC QLQ -C30 questionnaire

– Biomarkers

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Subject Participation

4-week Screening period

Treatment until disease progression provided tolerating treatment If low tolerability, docetaxel can be stopped In the combo arm. treatment with ganetespib may be continued

in the absence of progression and per investigator’s assessment of potential for clinical benefit with continued treatment

Disease assessments q6wks from date of randomization Assessments are not linked to treatment schedules adherence to assessment schedule is critical

Survival follow-up ~q6wks after last dose until death or lost to follow-up

Crossover from Arm A to Arm B is not permitted at any time

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Key Eligibility Criteria

Pathologically confirmed diagnosis of NSCLC

Stage IIIB or IV NSCLC

ECOG Performance Status 0 or 1

Prior therapy defined as: One prior systemic therapy for advanced disease that includes:

A platinum-based chemotherapy; or EGFR TKIs for mEGFR disease

Maintenance therapy allowed provided that it was started no more than 4 weeks after the last dose of prior therapy.

Prior adjuvant or neoadjuvant therapy is allowed

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Key Eligibility Criteria (cont.)

Measurable disease Modified RECIST 1.1

Disease progression following 1st line treatment: Any new lesion or Increase of ≥ 20% of one or more existing lesions. Radiological nadir, and disease progression scans

Radiologically & clinically stable CNS metastases Patients must be off steroids for at least 3 months prior

to randomization

Adequate hematological, hepatic and renal functions

Archived tumor tissue (tissue block or at least 10 unstained slides)

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Key Eligibility Criteria (cont.)

No active or untreated CNS metastases

At least 2 weeks since prior local RT

At least 4 weeks since prior surgery

Normal cardiac function LVEF <50% at baseline Baseline QTc > 470 msec No history of serious cardiac illness:History of documented CHF, New York Heart Association class

II/III/IV, w/a history of dyspnea, orthopnea or edema requiring current tx with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics.  NOTE: Use of these medications for the treatment of hypertension is allowed

Summary of Key Schedule of Events

4 weeks

Screening

death/lost FU

Pre-screening • Disease progression?• Determine eligibility

Consent

Cycles/3 wks

Treatment

Demography, C/O, PE, PS, vital signs (VS)Hem, chemistry, LDH, s pregnancy testECG, MUGA/ECHOConc medicationAdverse events

Send tumor tissues BARCCT & bone scans Bioclinica

QoL - EORTC QLQ -C30

PK - Cycle 1&2 D1

SafetyD1- PS, ECGD1/15 - VS, hem, chemq4 cycles - LVEF

CT scansq6 wks – regardlessBone/brain as indicated

QoL, Wk 6/12Biomarkers – C1 D1/15, C2 D1LDH, - D1 each cycle

R

PGx once any time

Follow up Withdrawal

AEs/SAEs 30D from last dose

CT scans q6 wksOnly in none DP

Subsequent anticancer Rx

Survival status q6wks

PE, PS, VS, ECGHem, chemAEs/SAEs

End of Rx

Dosing

RandomizationARM A

Day 1

Docetaxel 75 mg/m2

Day 8 Day 15

Day 22

Cycle 1 Cycle 2 etc..

Docetaxel 75 mg/m2

Day 1

Ganetespib150 mg/m2

RandomizationARM B

Docetaxel 75 mg/m2

Day 8 Day 15

Ganetespib150 mg/m2

Day 22

Ganetespib150 mg/m2

Docetaxel 75 mg/m2

Cycle 1 Cycle 2 etc..

1 hr rule: 1 hr infusion, 1 hr rest

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Dose Modifications Due To Toxicity – General Guidelines

Up to 14 days treatment delay allowed for resolution of toxicity Consult with Medical Monitor for dose delay > 14 days or

additional reduction Unplanned treatment interruption for more than 4 weeks (e.g.,

planned travel for vacation) patient withdrawal

A single dose reduction to 80% permitted

Appropriate supportive care should be provided for the management of drug related toxicities

Grade 1 & 2 toxicities Dose modification not required Follow docetaxel labeling and/or local institutional practice for

drug related hematological & non hematological AEs

Refer to the protocol guidelines for dose modification/delay of ganetespib and/or docetaxel

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Events of Interest – Diarrhea

Manage diarrhea proactively for all subjects Expected drug class effect, typically starts 2 to 3 hours following

ganetespib administration Follow ASCO guidelines for treating chemotherapy-induced diarrhea

Grade 1-2

Loperamide as an initial 4-mg dose, followed by 2-mg doses q 4 hours

Continue until subject is free from diarrhea for 12 hours

Stop lactose-containing products, adequate hydration, frequent small meals, etc.

Grade 3 or 4 or complicated Grade 1 or 2 (severe cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, frank bleeding, dehydration)

IV fluids as appropriate and prophylactic antibiotics

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Events of Interest - Hypersensitivity

Mild or moderate symptoms:

Stop infusion

IV dexamethasone 10 mg & diphenhydramine HCl 25 - 50 mg

After recovery, resume infusion or re-schedule for treatment

Use premedication for subsequent infusion drug administrations

Severe symptoms

Stop infusion

Administer IV dexamethasone 10 mg & diphenhydramine HCl 25 - 50 mg

Add adrenaline (1:1000) or bronchodilators, if indicated

Stop treatment if severe symptoms recur

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Screening Procedures (4 wks prior to D1)

Consent

Demography - gender, date of birth, and race

Medical Hx including prior anti-cancer therapies

Complete physical examination, including weight and height, and neurologic assessment.

If clinically indicated, neurological assessments may be repeated during and after treatment

Vital signs- temperature, blood pressure and heart rate

ECOG performance status

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Screening Procedures (cont.)

Local Laboratory Assessments CBC with differential Chemistry Serum pregnancy (women of childbearing potential) Must be documented negative for eligibility

Central Laboratory Assessments - LDH and LDH isoforms Send tissue block or minimum 10 slides

12-lead ECG

MUGA or ECHO

Record medications received w/in 14 days prior to randomization

Review of adverse events (from date of informed consent)

Subject’s completion of EORTC QLQ -C30 questionnaire

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Disease Assessment at Screening

All baseline scans must be sent electronically to independent imaging vendor for QC prior to randomization

Perform disease assessment closer to randomization (2wks prior to randomization)

CT scans of chest and upper abdomen MRI brain

Repeated brain scan only when clinically indicated Bone scan

skull, total spine, clavicle, ribs, pelvis and long bones repeat bone scans

If clinically indicated (e.g., localized bone tenderness, elevated calcium levels and ALP

bone lesions at baseline, repeat every 12 weeks

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Randomization

Subjects should continue to meet eligibility criteria prior to

randomization

Randomization via IVRS/IWRS to be performed within 3 calendar

days prior to Day 1 dose

4 stratification variables entered into system:

ECOG score

Histology

Screening LDH (based on central lab results)

time since initial diagnosis

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Treatment Period Procedures - Safety

D1 Each Cycle:

– PE, body weight, PS, and 12-lead ECG

D1 and D15 Each Cycle:

– Hematology and chemistry

– Vital signs (temperature, BP and HR)

Every 4 Cycles (~q12 wks)

– ECHO or MUGA

– Repeat LVEF within 1 to 2 wks if >20% relative decrease from baseline

Ongoing:

– Review AEs

– Review/record all concomitant medications added and/or changed

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Treatment Period Procedures - Efficacy

Every 6 wks from day of Randomization (regardless of dosing

schedule)

CT/MRI scans of the chest and upper abdomen

Adhere to the assessment schedule to avoid assessment bias

Same imaging technique is utilized throughout the study

Brain and bone scans repeated as clinically indicated

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Treatment Period Procedures - QOL

At Wks 6 and 12 (~D15 of Cycles 2 and 4)

• Completion of EORTC-QLQ-C30– Instrument must be completed by the subject

9090-08: Treatment Period Procedures - PK

Pharmacokinetic Assessments Cycle 1 Day 1 and Cycle 2 Day 1

Arm A (docetaxel only):

• 5 mL sample at 1 to 2 minutes prior to end of docetaxel infusion

Arm B (ganetespib + docetaxel):

• 5 mL sample at 1 to 2 minutes prior to end of ganetespib infusion

• 5 mL sample at 1 to 2 minutes prior to end of docetaxel infusion

All blood draws for pharmacokinetics are to be done contralateral to the

infusion

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Treatment Period Procedures - Biomarkers

Pre-dose: Cycle 1 Day 1/15; Pre-dose Cycle 2 D1

– Plasma samples for biomarker analysis

Pre-dose D1 of each treatment cycle

– Blood sample for total LDH and LDH isoforms

Single collection (any time during subject participation)

– Whole blood sample for pharmacogenetic analysis

– Sample is optimally collected at earliest opportunity, but may be collected at any time during the study

• Participation requires separate consent and does not preclude participation in the core clinical study

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End of Treatment Procedures

W/in 30 days of decision to stop treatment

Physical exam

Vital signs

ECOG PS

12-lead ECG

Laboratory Assessments Complete hematology and clinical chemistry Serum pregnancy test

Review of adverse events and concomitant medications

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Survival and Follow-Up Assessments

CT/MRI (chest and upper abdomen) q6wks from date of last tumor assessment until PD or until beginning a new cancer Rx

Only for treatment discontinuation for reasons other than progressive disease:

Survival status: ~q6wks from date of last study drug administration (telephone or visit) until death / lost to follow-up

Collection & follow-up of AEs or SAEs until resolution or maximum of 30 days after discontinuation of the study drug

Collection of any subsequent anti-cancer therapy received after stopping study drug

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Subject Withdrawal Criteria

Treatment Withdrawal

Objective disease progression

Patients who continue to derive clinical benefit may remain on treatment at the discretion of the investigator

AE (including intercurrent illness or unacceptable toxicity)

Subject request/withdrawal of consent from treatment.

Investigator's decision (with documentation of reason)

Discontinuation of the study by the sponsor

Study Withdrawal Subject request/withdrawal of consent. Lost to follow-up Death Discontinuation of the study by the sponsor

Concomitant Medications

Prior treatments

– Record all treatments received within 14 days prior to randomization: Name of the drug, route, indication, start and stop date

Prohibited concomitant medications

– Other anticancer therapies

Drug-drug interaction - Avoid or use with Caution

– Medications associated with QTc prolongation

– Substrates of CYP3A4 or CYP2C19

Permitted concomitant medications

– Erythropoietin or growth factor support; red blood cell transfusions.

– Steroids• Inhaled, topical, or for physiologic replacement, or for short term treatment

• Standard 3-5 day course of dexamethasone for prevention of chemotherapy- induced nausea/vomiting

• Glucocorticoid daily doses (oral) 1.5 mg dexamethasone (or equivalent)

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RECIST v1.1Key Considerations

Why Is Tumor Evaluation Critical?

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Start ofTreatment

Response Progression Death

Time to Response

Duration of Response

Time to Progression

Survival

Categorizing Tumors at Baseline

Measurable Lesions that can be accurately measured in at least one

dimension [longest diameter (LD) to be recorded] >10mm by CT scan

Pathologically enlarged lymph nodes, ≥15 mm in the short axis by CT scan

Non measurable All other lesions, including lesions too small to be classified as

measurable, and truly non-measurable lesions (e.g. bone lesions, ascites, pleural effusion, leptomeningeal disease, etc)

Measured as close as possible or at least within 2 weeks prior to first dose

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Baseline Documentation of Target and Non-target Lesions

TARGET: All measurable lesions up to a maximum of 5 per organ and 10 in total, representative of all involved organs

select on basis of size suitability for accurate repeat measurement

A sum of the diameters for all target lesions reported at each time point

Baseline sum of diameters is reference for objective tumor response

NON-TARGET: all other lesions and sites of disease

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Target Measurement Rules for Splitting Lesions

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• If a previously confluent lesion separates to form discrete

lesions, the LD of each lesion will be measured and next summed

and recorded under the original lesion number.

– The lesion code under the original number should be “split

or divided”

Baseline Week 12

1

105 mm

1a

37mm + 45mm = 82mm

Lesion 1 = 82mmLesion Code = Split/Divided

Target Measurement Rules for Merging Lesions

34Baseline Week 12

1

105 mm

1

37mm

2

If lesions become confluent, measure the LD of the confluent mass and

record this measurement as the longest diameter under the smaller

lesion number. “0” mm will be entered for the other target lesion(s).

– The lesion code under the original number should be “merged or

coalesced”

45mm Lesion 1 = 105mmLesion Code = merged/coalescedLesion 2 = 0mmLesion Code = merged/coalesced

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Image Resolution

CT slice thickness recommended to be no greater than 5 mm Resolution as slice thickness Resolution as slice thickness

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Overall Response; Best Overall Response (BOR)

Difference between overall response and BOR

Overall Response at a Timepoint is the time when you assess if

the patient should continue in the study

Best Overall Response is the best achieved response during the

study

Refer to the Protocol for the Table of BOR

Confirmation of Response

No confirmation scans are required

Will be corrected in the planned protocol amendment

Understanding the Definitions -Overall Response vs Best Overall Response

Overall (Visit) Response

Target Non-Target

Target Non-Target

New Target

Non-Targe

t

New

PR SD No

Baseline Week 6 visit Week 12 visitVisits

Response by lesion category

PDPR

Lesions category

-------

-------

PD SD No

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Evaluation of Target Lesions

Response Definition Reference

CR Disappearance of all target lesions.

Any pathological lymph nodes (target or non-target) have reduction in SA to <10 mm

Baseline

PR 30% decrease SLD Baseline

SD Not CR, PR, PD Nadir

PD 20% increase SLD

New lesions

Nadir

Non-Evaluable

Inadequate/missing images; inability to visualize > 25% of target disease

Baseline

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Evaluation of Non-Target Lesions

Response Definition Reference

CR Disappearance of all non-target lesions

All lymph nodes < 10 mm SA

Baseline

Non-CR/Non-PD

Persistence of one or more non-target lesion(s).

Baseline

PD Unequivocal progression Nadir

Non-Evaluable

Inadequate or missing images; inability to visualize > 50% of non-target disease.

Baseline

Potential Problems

When measurements are not present for a visit for any lesions being

followed, then a response assessment cannot be completed and

response is recorded as Unknown

For each lesion, the method of measurement must remain the same

during the study or the lesion becomes non-evaluable for the visit

and response is Unknown

NEW lesions must not be added to the sum of target lesions

If follow-up scans are incomplete for visits where imaging is

expected, the only possible overall response determination is PD or

“unknown.”

Questions?