Pembrolizumab vs Topotecan in Patients With Small Cell Lung Cancer

This is a multi-institutional, randomized, open-label phase II study of pembrolizumab compared to topotecan, administered to patients with SCLC who have progressed or relapsed after first-line treatment with etoposide and platinum. Patients will be randomized in a 2:1 fashion to receive pembrolizumab or topotecan. Participants in the topotecan arm that progress will be allowed to cross-over to the pembrolizumab arm.

Patients who meet the eligibility criteria and are randomized to one of the treatment arms, will receive either topotecan alone intravenously at 1.25 mg/m2 on days 1 to 5 of a 21-day cycle or pembrolizumab alone administered intravenously at 200mg every 21 days.

During the study period, patients will be evaluated clinically by physical exam and with routine blood work every 21 days. Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. Pre-specified adverse events of clinical interest include: 1) Grade ≥ 2 diarrhea, 2) Grade ≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 2 hepatitis 5) Grade ≥ 3 hypo- or hyperthyroidism.

Patients will be evaluated every 6 weeks (42 ± 7 days) with radiographic imaging to assess response to treatment. Investigators will make all treatment-based decisions using RECIST 1.1. Patients will continue to receive topotecan or pembrolizumab every three weeks until documented disease progression, unacceptable side effects, intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the patient, patient withdraws consent, pregnancy of the patient, non-compliance with trial treatment or procedure requirements or administrative reasons. Patients on the topotecan arm who progress on study will be allowed to cross-over to the pembrolizumab arm.

After the end of treatment, each patient will be followed for a minimum of 30 days for adverse event monitoring. Serious adverse events will be collected for up to 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier. Immune related serious adverse events will be followed for 90 days after end of treatment. Subjects who discontinue treatment for reasons other than disease progression will have posttreatment follow-up every 6 weeks for disease status until progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed by telephone contact every 3 months for overall survival until death or withdrawal of consent.

Although subjects will be enrolled regardless of PD-L1 status, subjects will be required to provide tissue of a tumor lesion (either archived tissue or a new biopsy before initiating therapy). Tumor samples will be required before initiating therapy (preferably a new specimen) and a repeat biopsy will be performed, if clinically feasible, on-treatment (during weeks 4 to 6) for those in the pembrolizumab arm and at the time of disease progression for those in the topotecan arm. PD-L1 expression status by immunohistochemistry will be determined on tumors at baseline, on treatment and at the time of topotecan progression. Numerous other correlative studies also will be performed, as outlined below. Peripheral blood mononuclear cell samples will be collected at screening, at day 1 of cycles 1, 2 and 3, and at the time of each imaging study (while on study), for characterization of T-cell phenotypes to understand how changes may correlate with clinical response.

Eligibility Criteria:
Inclusion Criteria:

In order to be eligible for participation in this trial, the patient must:

1. Have histologically or cytologically confirmed small cell lung cancer. Confirmation will be done at each participating site.
2. Have relapsed or progressed after only one prior chemotherapy regimen, which must have been an etoposide-platinum doublet. Eligible patients will be defined as follows:

   "Sensitive" Disease: Patients who had one previous line of chemotherapy and relapsed after \> 60 days of completion of treatment.

   "Refractory" Disease: Patients with no response to first-line chemotherapy or progression \>60 days after completing treatment.
3. Be ≥ 18 years of age on day of signing informed consent.
4. Have a life expectancy of at least 3 months.
5. Have a performance status of ≤ 1 on the ECOG Performance Scale.
6. Have measurable disease based on RECIST 1.1.
7. Have a tumor tissue specimen available from either a core or excisional biopsy. The tumor specimen should be of adequate size and tumor cellularity to perform whole exome sequencing and immunohistochemistry. In subjects for whom newly obtained samples cannot be obtained (e.g. tumor inaccessible or safety concern), archived tissue may be submitted, if it otherwise satisfies all specimen criteria. Archival samples must have been obtained within 42 days prior to signing consent (please refer to section 12.1 of protocol).
8. Demonstrate adequate organ function as defined in Table 1.

   Table 1. Adequate Organ Function Laboratory Values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8 g/dL (without transfusion) Renal Serum creatinine

   OR

   Glomerular Filtration Rate (GFR) ≤1.5 X upper limit of normal (ULN)

   OR

   GFR ≥60 mL/min\* for patient with creatinine levels \> 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN

   OR

   Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN

   OR

   ≤ 5 X ULN for patients with liver metastases Albumin ≥ 2.5 mg/dL

   \*GFR should be calculated per institutional standards.
9. Female patients of childbearing potential should have a negative urine or serum pregnancy within 72 hours of starting treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female patients of childbearing potential must be willing to an adequate method of contraception as outlined in Section 14.4.1 - Contraception for the course of the study through 120 days after the last dose of study medication (see Section 13.4.1). Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Male patients must agree to use an adequate method of contraception as outlined in Section 14.4.1 - Contraception - starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

* The patient must be excluded from participating in the trial if the patient:

  1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 14 days of the first dose of treatment.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  3. Has had a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 14 days earlier.
  4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

     Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
  5. Has undergone major surgery, he/she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  6. Has a known additional malignancy that is progressing or requires active treatment.
  7. Has known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
  8. Has known carcinomatous meningitis.
  9. Has an active autoimmune disease requiring systemic treatment in the past 2 years or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
  10. Has evidence of interstitial lung disease, or history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
  18. Has received a live vaccine within 30 days prior to the planned first dose of study therapy.

      Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  19. Has a known history of active TB (Bacillus Tuberculosis).
  20. Hypersensitivity to pembrolizumab or any of its excipients.