Randomized Phase II Study of Single Agent OSI-906 Versus Topotecan for Relapsed Small Cell Lung Cancer (SCLC)

• Number of Participants With Serious Adverse Events [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: Yes ]
  Toxicity from this trial will be collected on all patients. Simple descriptive statistics will be utilized to display the data on toxicity seen from OSI-906 and topotecan. Toxicities will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.
• Overall Survival (OS) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The OS, defined as the time from study enrollment to death from any cause, will be summarized similarly to PFS utilizing the K-M method.

  The above described analyses will be repeated based on stratification factors (treatment response and Eastern Cooperative Oncology Group [ECOG] Performance Status [PS]) if appropriate and enough numbers enrolled.

• Overall Response Rate (ORR) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The overall response rate (ORR= complete response [CR] + partial response [PR])and disease control rate (DCR=CR+PR+stable disease[SD]) rates will be summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.

  The above described analyses will be repeated based on stratification factors (treatment response and ECOG Performance Status [PS]) if appropriate and enough numbers enrolled.

• Disease Control Rate (DCR) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The overall response (ORR=CR+PR)and disease control (DCR=CR+PR+SD) rates will be summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.

  The above described analyses will be repeated based on stratification factors (treatment response and ECOG Performance Status [PS]) if appropriate and enough numbers enrolled.

• Number of Participants With Serious Adverse Events [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: Yes ]
  Toxicity from this trial will be collected on all patients. Simple descriptive statistics will be utilized to display the data on toxicity seen from OSI-906 and topotecan. Toxicities will be assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.
• Overall Survival (OS) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The OS, defined as the time from study enrollment to death from any cause, will be summarized similarly to PFS utilizing the K-M method.

  The above described analyses will be repeated based on stratification factors (treatment response and Eastern Cooperative Oncology Group [ECOG] Performance Status [PS]) if appropriate and enough numbers enrolled.

• Overall Response Rate (ORR) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The overall response rate (ORR= complete response [CR] + partial response [PR])and disease control rate (DCR=CR+PR+stable disease[SD]) rates will be summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.

  The above described analyses will be repeated based on stratification factors (treatment response and Eastern Cooperative Oncology Group [ECOG] Performance Status [PS]) if appropriate and enough numbers enrolled.

• Disease Control Rate (DCR) [ Time Frame: Study duration - approximately 30 months ] [ Designated as safety issue: No ]

  The overall response (ORR=CR+PR)and disease control (DCR=CR+PR+SD) rates will be summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.

  The above described analyses will be repeated based on stratification factors (treatment response and Eastern Cooperative Oncology Group [ECOG] Performance Status [PS]) if appropriate and enough numbers enrolled.

The purpose of this study is to evaluate how OSI-906 compares to Topotecan in trying to slow down the growth and/or progression of the tumors of participants with relapsed or recurrent Small Cell Lung Cancer.

This study also plans to find out what effects, good or bad (side effects), OSI-906 has on participants and or Small Cell Lung Cancer. The study will also investigate if some proteins measured in the blood or tumor and some imaging features obtained from computed tomography (CT) scans can help predict whether OSI-906 or topotecan will be effective against Small Cell Lung Cancer.

Coordinating Center: Southeast Phase 2 Consortium (SEP2C) Moffitt Cancer Center 12902 Magnolia Drive Tampa, FL 33612

Once patients have been appropriately consented and registered on trial, they will be randomized in a 2:1 ratio, either to the experimental OSI-906 arm or the standard topotecan arm. Randomization will be performed at the Moffitt Cancer Center (MCC) by the Consortium Coordinator. Randomization will be accomplished through MCC's Automated Patient Registration and Treatment Randomization System (APRTRS). APRTRS is a web-based database system that provides centralized subject registration and treatment randomization for research studies. This system provides an automated method for single or multi-center clinical trials to centrally register and randomize subjects.

• Drug: Topotecan

  Patients will be treated with either oral or IV topotecan (treating oncologist's choice) at doses of 2.3 mg/m^2/d PO or at doses of 1.5 mg/m^2/d IV, given as a 30-minute infusion, respectively. The calculated daily oral dose should be rounded to the nearest 0.25 mg. Each treatment will be given for 5 consecutive days, repeated every 21 days.

  Cross over to OSI-906 will be allowed at the time of progression of disease, for those patients randomized to topotecan. Initiation of OSI-906 after the crossover is contingent to the fulfillment of the same eligibility criteria for initiation of OSI-906 used in the experimental arm.

  Other Name: Hycamtin®
• Drug: OSI-906
  The starting daily oral dose of OSI-906 chosen for our study is 150 mg twice a day (BID) continuing for 21 days (150 mg orally (PO) BID, daily every 21 days/3 weeks cycle).
  Other Names:

  • TKI
  • Tyrosine Kinase Inhibitor
  • Insulin Growth Factor-1 Receptor
  • IGF-1R
  • NSC-751082

• Active Comparator: Arm A - Topotecan Treatment
  Intervention: Drug: Topotecan
• Experimental: Arm B - OSI-906 Treatment
  Intervention: Drug: OSI-906

Inclusion Criteria:

• Histologically or cytologically confirmed SCLC
• Patients must have measurable disease as defined in the protocol document. At least one lesion that can be accurately measured is required.
• Must have progression of disease after receiving ONLY 1 previous platinum-containing regimen. Prior treatment with biological response modifiers or targeted agents will NOT count towards this requirement. Previous topotecan or any type of pharmacologic IGF-1R inhibition are NOT allowed.
• Life expectancy > 6 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; Karnofsky ≥60%
• Adequate hematologic (bone marrow), hepatic and renal function as defined below (within 4 weeks prior to enrollment): leukocytes (WBC) ≥3,000/mcL OR absolute neutrophil count (ANC) ≥1,500/mcL AND platelets ≥100,000/mcL; total bilirubin within normal institutional limits (NIL); aspartate aminotransferase (AST)[serum glutamic-oxaloacetic transaminase (SGOT)] / alanine aminotransferase (ALT)[serum glutamic pyruvic transaminase (SGPT)] ≤2.0 times institutional upper limit of normal (ULN) without demonstrable liver metastases OR < 5.0 times ULN within liver metastases present; Serum creatinine within NIL OR measured/calculated creatinine clearance (CrCl) ≥60 mL/min/1.73 m^2 for patients with creatinine levels above NIL; Fasting blood glucose <160 mg/dL at baseline
• Patients on oral antihyperglycemic therapies may be enrolled provided they have been taking a stable dose of these medications for ≥2 weeks at the time of randomization.
• Prior radiation is permitted IF the site(s) of measurable disease has progressed since prior irradiation and radiation is completed at least 2 weeks before initiation of drug treatment (stereotactic radiotherapy excluded).
• Patients with central nervous system (CNS) metastases are ELIGIBLE, provided that prior to drug treatment, the metastases have been treated, remain clinically or radiographically stable and the patient has no significant neurologic symptoms.
• Patients must NOT have prior malignancy EXCEPT for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for ≥ 3 years.
• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. WOCBP must provide a negative pregnancy test (serum or urine) within 14 days prior to registration.
• Available archival tumor tissue is NOT mandatory for enrollment (will be requested).
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Receiving any other investigational agents
• Patients with CNS metastases are NOT EXCLUDED, provided that prior to drug treatment, the metastases have been treated, remain radiographically stable and the patient has no significant neurologic symptoms.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-906 or other agents used in the study (topotecan)
• The primary route of metabolism of OSI-906 involves CYP1A2. While CYP1A2 inhibitors/inducers are not specifically excluded, investigators should be aware that the metabolism and consequently overall pKs of OSI-906 (OSI-906 exposure) could be altered by concomitant use of these drugs (inhibitors, inducers and/or other substrates of CYP1A2). Exception: Potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited. OSI-906 is a moderate inhibitor of CYP2C9. While CYP2C9 substrates are not specifically excluded, investigators should be aware that levels of drugs metabolized by CYP2C9 may be increased by the concomitant administration of OSI-906. Caution should be used when administering CYP2C9 substrates to study patients. Lists including medications and substances known or with the potential to interact with CYP1A2 and CYP2C9.
• P-glycoprotein inhibitors (e.g., cyclosporine A, elacridar, ketoconazole, ritonavir, and saquinavir) can cause significant increases in topotecan exposure. The concomitant use of p-glycoprotein inhibitors with topotecan capsules is not allowed. Enzyme inhibition by Topotecan has not been evaluated in vivo but in vitro inhibition studies indicate that the activities of these enzymes were not altered by topotecan. Hence there are no specific exclusions for such medications that are metabolized through this pathway.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, significant cardiac disease (i.e: symptomatic congestive heart failure, unstable angina pectoris, symptomatic or lifethreatening cardiac arrhythmia), or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or breast-feeding women are excluded from this study. Prior negative pregnancy test is required.
• Human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for Pharmacokinetic (pK) interactions with OSI-906. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• Patients in the following scenarios are also excluded: corrected QT interval (QTc interval) >450 msec at baseline; concomitant drugs that prolong the QTc interval; Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to randomization; Fasting blood glucose ≥160 mg/dl at baseline, these patients can initiate oral antihyperglycemic therapies and be retested or rescreened 2 weeks later to meet baseline fasting blood glucose criteria; Concomitant use of insulin or insulinotropic medications.
• Patients with cirrhosis of the liver are excluded from this study.
• Archival tumor tissue is NOT mandatory for enrollment, but will be requested.