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Pembrolizumab vs Topotecan in Patients With Small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02963090
Recruitment Status : Active, not recruiting
First Posted : November 15, 2016
Last Update Posted : July 30, 2019
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Alliance Foundation Trials, LLC.

Brief 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.

Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Drug: Topotecan Drug: Pembrolizumab Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study Evaluating Pembrolizumab vs Topotecan in the Second-Line Treatment of Patients With Small Cell Lung Cancer
Actual Study Start Date : May 20, 2017
Actual Primary Completion Date : May 20, 2019
Estimated Study Completion Date : August 20, 2019

Arm Intervention/treatment
Active Comparator: Topotecan
Topotecan IV at 1265mg/m^2 Days 1-5 of every 21 day cycle
Drug: Topotecan

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.

Other Name: hycamtin

Drug: Pembrolizumab
200 mg IV every 21-days until progression of disease or unacceptable toxicities.
Other Names:
  • Keytruda
  • MK-3475

Experimental: Pembrolizumab
Pembrolizumab IV 200mg infusion Day 1 of every 21 day cycle
Drug: Pembrolizumab
200 mg IV every 21-days until progression of disease or unacceptable toxicities.
Other Names:
  • Keytruda
  • MK-3475

Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: The primary endpoint will be defined as the time between randomization and disease progression or death of all causes, whichever comes first. Randomization, treatment and safety follow up is defined as 30 months. ]
    This phase II study will determine if there is a benefit in progression free survival (PFS) for SCLC patients receiving pembrolizumab (Experimental arm) as compared to topotecan (Control arm) in the second-line settingSCLC patients receiving pembrolizumab (Experimental arm) as compared to topotecan (Control arm) in the second-line setting

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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


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


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


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


    ≤ 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02963090

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United States, Minnesota
Metro MN Community Oncology Research Consortium
Saint Louis Park, Minnesota, United States, 55416
United States, Ohio
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Alliance Foundation Trials, LLC.
Merck Sharp & Dohme LLC
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Principal Investigator: Monica Bertagnolli, MD Alliance Foundation Trials
Study Chair: Thomas Stinchcombe, MD University of North Carolina, Chapel Hill
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Eckardt J, Gralla R, Palmer MC, et al. Topotecan as second-line therapy in patients with small cell lung cancer: a phase II study. Ann Oncol 1996;7:107 (abstr 513).
Depierre A, von Pawel J, Hans L, et al. Evaluation of Topotecan (Hycamtin) in relapsed small-cell lung cancer (SCLC): A multicenter phase II study. Lung Cancer 1997;18:35 (abstract 126).
Eckardt J, Depierre A, Ardizzoni A, von Pawel J, Fields SZ. Pooled analysis of topotecan in the second-line treatment of patients with sensitive small cell lung cancer. Proc Am Soc Clin Oncol 1997;16:452a (abstr 1624).
Koschel R, Huber RM, Gatzemeier U, et al. Topotecan in Second-Line Treatment of Small Cell Lung Cancer Reduced Toxicity with Individualized Therapy. Lung Cancer 2000;29:42 (abstract 135).
Ott PA, Elez E, Hiret S, et al. Pembrolizumab for Extensive Stage Disease SCLC: Efficacy and Relationship with PD-L1 Expression. 16th World Conference on Lung Cancer 2015;Abstract 3285.
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.
Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Müller C, Di Cerbo V, Schildhaus HU, Altmüller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Böhm D, Ansén S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grütter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sänger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Büttner R, Wolf J, Nürnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012 Oct;44(10):1104-10. doi: 10.1038/ng.2396. Epub 2012 Sep 2.
Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 Jul 11;499(7457):214-218. doi: 10.1038/nature12213. Epub 2013 Jun 16.
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Responsible Party: Alliance Foundation Trials, LLC. Identifier: NCT02963090    
Other Study ID Numbers: AFT-17
First Posted: November 15, 2016    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alliance Foundation Trials, LLC.:
small cell lung cancer
lung cancer
Additional relevant MeSH terms:
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Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Antineoplastic Agents, Immunological
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action