Early Clinical Trials with Molecularly Targeted …...Molecularly Targeted Therapies Gilberto Schwartsmann What are the basics of clinical trial design? Presented By Jordan Berlin

Design of Clinical Trials withMolecularly Targeted Therapies

Gilberto Schwartsmann

What are the basics of clinical trial design?

Presented By Jordan Berlin at 2016 ASCO Annual Meeting

Advances in molecular biology

• Molecularly targeted agents (MTAs)against specific oncogenic drivers.

• MTAs differ from cytotoxics in toxicityprofiles and availability of predictivebiomarkers.

• Early trials are evolving to adapt to MTAs!

The lines have become blurred

Presented By Jordan Berlin at 2016 ASCO Annual Meeting

Example 1

Background

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Dosing schedule and toxicities

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Phase II

IIa: Pilot to evaluate efficacy (and safety) in selectedpatient populations, to define dose-response, typeof patients, frequency of dosing, etc.

IIb: Well controlled trials for efficacy (and safety) inspecific disease, most rigorous demonstration ofefficacy, pivotal trials.

Example 2

Rationale

Presented By Hans-Joachim Schmoll at 2016 ASCO Annual Meeting

“PAPAGEMO”: Pazopanib vs. Pazopanib+ Gemcitabine in refractory soft tissue sarcoma:<br />A randomized phase II trial of the AIO


“PAPAGEMO”- Trial design<br />Multicenter open-label prospective randomized phase II trial


Endpoints


Conclusion


Example 3

Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer: Results from the phase I/II CheckMate 032 study

Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

Study design


Eligibility criteria


Study endpoints


Treatment-related AEs


Tumor burden reduction in target lesions


Time to and duration of response


Progression-free survival


Overall survival


Phase IIIIIIa: Conducted after efficacy is demonstrated, butprior to regulatory submission of NDA (New DrugApplication). Includes patients for which the drug isintended; or special groups (p.e., renal failure).

IIIb: Conducted after regulatory submission of NDA,but prior to approval. Complete or supplementearlier trials, or directed to new type of trials (QoL,marketing).

Example 4

Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) - <br />CALGB 80802 (Alliance)

Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting

CALGB 80802 Study Schema


CALGB 80802 Study Objectives


CALGB 80802: Overall Survival by Treatment


CALGB 80802: Progression-Free Survival by Treatment


Summary


Overall Success at Phase II and III

Presented By George Sledge at 2016 ASCO Annual Meeting

Low Success Rate of Drug Approvals!

Likelihood of approval for drugs tested in phase I trials is6.7%, the lowest of all diseases*!

From 1998-2014, failure-to-success ratio ofinvestigational agents for melanoma was 14:1, and only10 of 177 agents for lung cancer were approved**.

Drug development in oncology takes 1.5 years longerthan in other diseases (slow recruitment, low PS andlonger follow-up needed)***.

*Hay, M. et al. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51 (2014). **PharmaceuticalResearch and Manufacturers of America. Researching Cancer Medicines: Setbacks and Stepping Stones, http://www.phrma.org/sites/default/files/pdf/2014-cancer-failures-setbacks.pdf (2014). *** DiMasi, J. A. & Grabowski, H. G. Economics of new oncology drug development. J. Clin. Oncol. 25, 209–216 (2007).

New Features in MTA Phase I trials

• New expedited approval to accelerate drugdevelopment requires efficacy in early phasetrials!

• Molecular tumor profiling for matched therapyand testing of drug combinations!

• The shift towards multi-institutional trialsand centralized management.

What Could Be Done to Improve Early Trials of MTAs?

• Safety is a key requirement

• Novel dose-escalation schemes?

• Improved patient selection?

• Pharmacokinetic/Pharmacodynamics?

Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of 3-6 patients, with 40% dose-step increments and no intra-patient dose escalation. Designs 2- 4 included only 1patient per cohort until 1 patient experienced DLT or 2 patients experienced grade 2 toxic effects (during their firstcourse of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100%dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted tostandard cohorts of 3-6 patients, with 40% dose-step increments. Designs 2 through 4 used intra-patient doseescalation if the worst toxicity is grade 0–1 in the previous course for that patient.

Conclusion: Accelerated titration (i.e., rapid intra-patient drug dose escalation) designs appear toeffectively reduce the number of patients who are undertreated, speed the completion of phase Itrials, and provide a substantial increase in the information obtained.

1997

1993

Methods: One hundred phase I studies were simulated by both standard and quantitative assessmentphase I designs. We compared MTD, frequency of 0 leukopenia and study size in the studies simulatedusing the standard design with those in the studies simulated using the quantitative assessment design.Results: The median MTD determined from the 100 studies was nearly identical for the two designs: 100and 95 mg/m2 per day for standard and quantitative assessment designs, respectively. However, the inter-study variation in the MTD was decreased in the quantitative assessment design. Moreover, the study sizewas significantly reduced (P<.0001), and the median percentage of patients treated at sub-toxic doses (noleukopenia) was significantly lower for the quantitative assessment design (44% versus 48%; P<.0001).Conclusion: Our results show clear evidence that a phase I study design using dose and toxicity data in arepetitive and quantitative manner can identify the MTD with more accuracy than the standard design.

Novel vs Classical Dose-Escalation

• The efficiency of novel dose-escalationdesigns was demonstrated in a study of 84phase I trials published between 2000 and2010*.

• Compared with traditional 3+3 strategy,newer designs explored a greater number ofdose levels (median of 6 vs 8-10) andachieved > mean MTD-to-starting-doseratio (ratios of 9 vs 22-30).

*Le Tourneau, C., Gan, H. K., Razak, A. R. & Paoletti, X. Efficiency of new dose escalation designs in dose-finding phase I trials of molecularly targeted agents. PLoS ONE 7, e51039 (2012)

Patient Selection• In most cases, an MTA is active in a

subgroup of patients who may beidentified using predictive biomarkers.

• The selection of patients based onmolecular profiling can be done by geneor protein expression or detecting genealterations (p.e., mutation, amplificationor translocation) in tumor tissue or DNA.

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PFS by independent review

PFS in overall population

Afatinib (n=242)

Cis/Gem(n=122)

Median, mo 11.0 5.6

HR (95% CI)P-value

0.28 (0.20-0.39)P<0.0001

PFS by investigator review

LUX-Lung 6: Primary End Point PFS by Independent and Investigator Review

No. at risk:Afatinib 242 208 166 126 89 60 35 12 4 0

Cis/Gem 122 70 25 8 1 0 0 0 0 0

No. at risk:Afatinib 242 211 178 157 124 87 49 23 10 1 0

Cis/Gem 122 75 31 13 3 2 0 0 0 0 0

PFS = progression-free survival; HR = hazard ratio. Wu et al. Lancet Oncol. 2014;15:213.

PFS in overall population

Afatinib (n=242)

Cis/Gem(n=122)

Median, mo 13.7 5.6

HR (95% CI)P-value

0.26 (0.19-0.36)P<0.0001

PFS

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

0

PFS (mo)

0 3 6 9 12 15 18 21 24 27

2%

Afatinib

Cis/Gem

30 6 9 12 15 18 21 24 27 30

PFS (mo)

PFS

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

0

Afatinib

Cis/Gem47%

2% 4%

56%

Recent Examples of Successful Use of Predictive Biomarkers in Phase I

• Phase I trials of crizotinib*, ceritinib** andalectinib*** in patients with EML4–ALKrearranged NSCLC

• Vemurafenib in patients with BRAF/V600E-mutant melanoma****

• The remarkable tumor responses in thesepatient subsets facilitated drug approval!

* Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010). ** Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014). *** Seto, T. et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol. 14, 590–598 (2013). **** Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

Limitations of Biomarkers

• Most cancers have multiple genetic aberrationsand the sensitivity to an MTA is likely modulated bymany factors.

• Identifying a reliable biomarker might be lessfeasible when an MTA interacts with severaltargets or pathways, as is the case with manytyrosine kinase inhibitors.

• Establishing a very strong scientific basis for thebiomarker with preclinical validation is, therefore,a prerequisite to avoid negative trials.

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Afatinib Is the First Irreversible ErbB Family Blocker

• Afatinib covalently binds and irreversibly blocks EGFR, HER2, and ErbB4

O

N

N

N

F

Cl

O

N

ON

N

S

O

N

S

O

N

N

N

F

Cl

O

O

N

ON

Afatinib

Afatinibcovalently bound

• ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

• Afatinib prevents ligand-dependent ErbB3 phosphorylation in preclinical studies

0 0 300 1000 300 100

– + – + + +

Afatinib (nM)

Heregulin

pErbB3

Anti-phospho-immunoblotting has shown that afatinib prevents ligand (heregulin)-

stimulated ErbB3 phosphorylation

Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.

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Inhibitory potency of afatinib, erlotinib, and gefitinib against ErbB family membersin cell-free kinase assays and cell proliferation assays of various human lungcancer cell lines (nanomolar concentration causing 50 % inhibition (Solca et al. JPharmacol Exp Ther, 2012; and Li et al. Oncogene, 2008)

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Molecular selectivityKinase panel 10 μM 0/50

PanLab 5 μM 3/62

CYP450 10 μM 0/6

Afatinib Is a Potent and Selective Inhibitor of EGFR, HER2, and ErbB4

Molecular potency and selectivity (IC50)

EGFR (nM) 0.5

HER2 (nM) 14

ErbB4 (nM) 1

HGFR (nM) >10,000

VEGFR2 (nM) >100,000

Afatinib selectively and potently blocks the ErbB family receptors

EGFR, HER2, and ErbB4

Afatinib is highly selective and does not inhibit a range of other kinases

significantly, even at 1000 times higher concentrations

IC50 = 50% inhibitory concentration; HGFR = hepatocyte growth factor receptor; VEGFR2 = vascular endothelial growth factor receptor 2.Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.

Biomarkers Need Optimal Collection, AssayPerformance, Reproducibility and

Standardization!

• That´s why a low percentage of MTAs weredeveloped with biomarker-based patient selection.

• In phase I studies, predictive value of biomarkersare studied as exploratory objectives.

• Examples: tumor PD-L1 expression in a subset ofpatients in phase I trial of nivolumab or tumorgenotyping for BRAF and NRAS mutations in phase Itrial of MEK inhibitor trametinib.

Anticancer Drug Developmentin 2016

• “Breakthrough therapy’ FDA designation to expedite drugdevelopment, obtaining early evidence of efficacy as a keycomponent of phase I studies.

• Tumor-specific expansion cohorts in phase I trials tofurther characterize safety and tumor response at therecommended dose for Phase II increased.

• Response rate contributed to over 75% of accelerated FDAdrug approvals from 2002 to 2012.

• For therapies with benefit across many tumor types,efficacy evaluation can lead to large phase I trials withmultiple expansion cohorts.

*Manji, A. et al. Evolution of clinical trial design in early drug development: systematic review of expansion cohort use in single-agent phase I cancer trials. J. Clin. Oncol. 31, 4260–4267 (2013). **Bugano, D. et al. Impact of phase 1 expansion cohorts on probability of success in phase 2 and time-to-drugapproval: analysis of 385 new drugs in oncology [abstract 237]. Eur. J. Cancer 50, 79–80 (2014).

Anticancer Drug Development in 2016

• Phase I of immunotherapies with anti-PD-1 andanti-PD-L1 in tumor-type-specific cohorts toassess efficacy in various settings.

• Selected phase I trial centers and disease-specific investigators to help enrolment indisease-based cohorts.

• The use of efficacy endpoints in phase I can leadto direct transition to phase III testing.Nivolumab and MEDI4736 are examples.

Target Modulation as Endpoint

• For MTAs, target modulation and downstream moleculareffects are more relevant surrogates of activity thantoxicity*.

• Levels of protein expression in tumor tissue by IHC beforeand after treatment, serum proteins, peripheral bloodmononuclear cells and imaging biomarkers are used.

• Circulating tumor cells and DNA will become essential as‘liquid biopsies’!**. Also, PK–PD and PK–toxicityrelationships are important, when drug concentration formaximal biological effects is known.

*Postel-Vinay, S. et al. Clinical benefit in phase-I trials of novel molecularly targeted agents: does dose matter? Br. J. Cancer 100, 1373–1378 (2009). **Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579–586 (2014).

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Presented By Luis Diaz at 2016 ASCO Annual Meeting

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Precision Medicine Trials• MTAs to target specific oncogenic drivers

and advances in next-generationsequencing (NGS) to rapidly interrogate thegenomic mutational profile of a tumor ledto Precision Cancer Medicine*.

• This concept can be described as thedelivery of patient-tailored therapy againstactionable molecular targets in order tomaximize antitumor activity whileminimizing toxicity.

*Meric-Bernstam, F. & Mills, G. B. Overcoming implementation challenges of personalized cancer therapy. Nat. Rev. Clin. Oncol. 9, 542–548 (2012).

MethodsBreast cancer patients with accessible metastases for biopsy in 18 centers in France. Therapeutic targets decided on thebasis of identified genomic alterations. Primary outcome to check the proportion of patients to whom a targetedtherapy could be offered.Results423 patients included and biopsy obtained from 407. Sequencing feasible in 67-70%. A targetable genomic alterationidentified in 46%, most frequently in PIK3CA (25%), CCND1 (19%) and FGFR1 (13%). In 39% rare genomic alterations(<5% of the general population), such as AKT1 mutations, EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET amplifications.

Therapy could be personalized in 13% of patients. Of the 43 patients who were assessable and received targetedtherapy, 9%) had objective response, and 21% had stable disease for more than 16 weeks. Grade 3 or higher adverseevents related to biopsy in only 1% of cases.

Lancet Oncol. 15, 267–274 (2014).

MTAs in Combination studies

• As most cancers are driven by multiplegenes and pathways, most benefits willbe derived from combinations of MTAswith other targeted therapy or standardchemotherapy.

• Thus, phase I trials of combinationtherapies are increasingly beingconducted.

Regulatory changes

• The development of a successfulanticancer drug from first-in-human studyto approval normally takes about 7 years!

• If an MTA has a well-defined mechanismbased on proof-of-concept studies,unprecedented clinical responses withminimal toxicity in early clinical trials andstrong predictive biomarker, the approvalprocess is being accelerated*.

*Sherman, R. E. et al. Expediting drug development — the FDA’s new “breakthrough therapy” designation. N. Engl. J. Med. 369, 1877–1880 (2013).

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Early Clinical Trials with Molecularly Targeted …...Molecularly Targeted Therapies Gilberto Schwartsmann What are the basics of clinical trial design? Presented By Jordan Berlin