Pembrolizumab vs Topotecan in Patients With Small Cell Lung Cancer
Condition: Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma
Intervention: Topotecan; Pembrolizumab
Intervention description: Topotecan at 1.25mg/m2 on days 1 to 5 every 21-days until progression of disease or unacceptable toxicities.
Patients with progression of disease by RECIST 1.1 will be allowed cross over to receive pembrolizumab 200 mg IV every 21-days for up to 1 year until progression of disease or unacceptable toxicities.; 200 mg IV every 21-days until progression of disease or unacceptable toxicities.
Intervention MeSH terms: Pembrolizumab; Topotecan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: SCLC; small cell lung cancer; lung cancer; topotecan; pembrolizumab

Summary:

      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.
    

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.