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M. Schell



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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-046 - A Novel Approach to Increase the Efficiency of Survival-Endpoint<br /> Phase II Trials. (ID 3153)

      09:30 - 09:30  |  Author(s): M. Schell

      • Abstract

      Background
      Lung cancer is the second most common cancer in United States. However, new molecular information whether arising from identification of key mutations, or Next Gen Sequencing (NGS) has lead to the fragmentation of this common disease into multiple and often very rare molecular subtypes. Even though this has enabled us to substantially improve survival in specific molecular subtypes with targeted agents, having sufficient numbers of patients to demonstrate the effectiveness of novel targeted therapies for each subtype has therefore become challenging, essentially impeding progress.

      Methods
      Use of sample size determination software allows for comparison of phase II trials with a target survival proportion at a given time T based upon Kaplan-Meier (KM) versus exponential (E) survival methods. This comparison was made in instances where the exponential distribution assumption is valid.

      Results
      The use of exponential survival fitting methods, in lieu of the currently implemented KM trial designs, to single arm phase II studies can routinely reduce patient numbers by 25-40% (Table) without compromising the statistical power. Another substantial advantage is that the variability in the survival information for the exponential fit estimate both before and after the median survival points is reduced. Since patient accrual is staggered ,this reduced variability allows for obtaining robust survival information with shorter follow up times T. Any additional follow-up beyond T only further improves the E estimate, but not the KM estimate. Thus, compared to the KM approach, the E approach will allow us to do single arm phase II trials with smaller numbers of patients without compromising statistical power. Robust survival estimates can also be achieved with shorter follow up periods. Figure 1

      Conclusion
      When conducting single arm phase II clinical trials with rare molecular entities of lung cancer, the exponential survival fitting method could replace the current standard approach. Robust survival information can be obtained with smaller numbers of patients and with shorter survival times. Detailed examples and analysis will be presented.

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    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.13-002 - Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients with Relapsed Small Cell Lung Cancer (SCLC) (ID 920)

      09:30 - 09:30  |  Author(s): M. Schell

      • Abstract

      Background
      SCLC typically presents with advanced (extensive stage) disease. Despite an initial response to chemotherapy, they all relapse and rarely survive beyond 2 years. Treatment of relapsed SCLC is limited (topotecan) and dependent on the response to initial chemotherapy (sensitive vs. refractory relapse). Downstream activation of PI3K-AKT, through IGF-1R pathway signaling plays a role in both, growth/survival and resistance to chemotherapy in SCLC. Growth inhibition and chemosensitization with IGF-1R inhibitors correlates with the PI3K-AKT inhibitory signaling and suggests AKT activation as a potential biomarker. OSI-906, is a well tolerated oral, small molecule, potent inhibitor of IGF-1R

      Methods
      A phase II randomized study comparing the efficacy of OSI-906 vs topotecan in patients with rSCLC is currently being conducted. Primary endpoint is PFS, summarized with the K-M method. An increase in median PFS from 2.5 to 4.175 months (in the experimental arm B) is proposed. A total of 95 patients are planned. Biomarkers of IGF-1R inhibition are explored in plasma, PBMC and using Radiomics. Eligible patients must have proven rSCLC, platinum sensitive (sen) or resistant (res) disease, ECOG PS 0-2 and adequate hematologic, renal and hepatic function. Fasting glucose <160 mg/dl, QTc < 450 msec and measurable disease by RECIST v1.1 are required. Pregnant, breast-feeding, diabetic and cirrhotic patients as well as those taking insulin/insulinotropic agents are excluded. Patients are randomized (2:1) to the experimental arm (B): OSI-906, 150 mg PO BID, until progression or to the standard arm (A): topotecan, 1.5 mg/m[2] IV daily x5 OR 2.3 mg/m[2] PO daily x5, for 4 cycles. Crossover to OSI-906 is allowed.

      Results
      Figure 1 Thirty-three patients have been enrolled; A=10 (res=6, PS 2=2) and B=23 (res=15, PS 2=4). M/F= 13/20; ECOG PS 0/1/2 = 8/19/6. Platinum sen/res = 12/21. Two patients were not treated (A/B = 1/1). Adverse events are described in Table 1. No responses have been observed. Only 2/6 and 1/15 patients in arms A and B respectively achieved SD at 6 weeks. Median PFS (A/B) was 2.1 (95% CI; 0.6, 3.6) and 1.3 (95% CI; 1.0, 1.4) months respectively (p = 0.0149). OS was not reached in arm A and 2.7 (95% CI; 1.5, …) months in arm B (p = 0.1716).

      Conclusion
      OSI-906 is safe in rSCLC patients. In our unselected, high risk population, efficacy in both arms, but particularly in arm B appears suboptimal. The study continues to accrue to reach the sample size and follow up time needed for more robust conclusions.