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DS-3201b and Irinotecan for Patients With Recurrent 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03879798
Recruitment Status : Recruiting
First Posted : March 19, 2019
Last Update Posted : March 4, 2022
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
This study will test the safety of the study drug, DS-3201b, given in combination with irinotecan to people who have recurrent small cell lung cancer (SCLC).

Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Drug: DS-3201b Drug: irinotecan Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: This study is a non-randomized phase I/II trial assessing the safety and tolerability of DS-3201b in combination with irinotecan in patients with recurrent small cell lung cancer.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of DS-3201b, an EZH1/2 Inhibitor, in Combination With Irinotecan in Patients With Recurrent Small Cell Lung Cancer
Actual Study Start Date : March 15, 2019
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: DS-3201b and Irinotecan
The first part of this study is a phase I trial to assess the safety and tolerability of DS-3201b in combination with fixed-dose irinotecan. The second part of this study will be an open label, single-arm phase II study of DS-3201b at the established recommended phase II dose (RP2D) in combination with fixed-dose irinotecan. Dose-Escalation, which enrolled a total of 12 patients at MSK, is completed. Phase 1 of this study determined that the highest and safest dose of DS-3201b in patients was 100 mg daily.
Drug: DS-3201b
100 mg daily

Drug: irinotecan
Irinotecan 125 mg/m^2 intravenously on days 1 and 8 every 3 weeks in a 21-day cycle.




Primary Outcome Measures :
  1. maximum tolerated dose (MTD) (Phase l) [ Time Frame: 1 year ]
    Will employ a standard 3-by-3 dose-escalation phase I study design to investigate the maximum tolerated dose (MTD) of DS-3201b in combination with fixed dose irinotecan. The study population for Phase I dose-escalation will include only patients who complete at least 1 full cycle of treatment (including the initial 7-day safety run-in and the complete 21-days of Cycle 1); only these patients will be considered evaluable for DLT and determination of the MTD.

  2. objective response rate (ORR) (Phase II) [ Time Frame: 1 year ]
    The Response Evaluation Criteria in Solid Tumors Group (RECIST v1.1) criteria will be used to evaluate the response to treatment



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

Inclusion Criteria:

  • Signed informed consent form (ICF)
  • Ability to comply with the study protocol as per the investigator's judgment
  • Age ≥ 18 years at the time of signing the ICF
  • Life expectancy ≥ 12 weeks
  • Karnofsky performance status ≥ 70%
  • Pathologically confirmed diagnosis of small cell lung cancer. Patients with a diagnosis of combined small cell lung cancer with other histologies may be considered for inclusion if the predominant histology is SCLC and only after discussion with the study PI.
  • Radiographically documented progression of disease after prior treatment with a platinum doublet regimen. Patients who received a platinum doublet regimen in combination with immunotherapy are still eligible for the study.
  • Measurable disease according to RECIST v1.1
  • Adequate tissue sample available for both IHC testing of IHC testing of SLFN11 and H3K27me3 and molecular profiling (archived tissue block or 20 unstained slides). Tissue sample can be either from an initial pre-platinum-based chemotherapy sample OR from a repeat biopsy sample after progression on platinum-based chemotherapy.
  • Adequate hematologic and end-organ function, as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:

    • Adequate bone marrow function as defined by:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/µL) without granulocyte colony-stimulating factor support
    • Hemoglobin ≥ 9 g/dL (transfusions to meet this criterion are allowed)
    • Platelets ≥ 150 x 10^9/L without transfusion
  • Adequate renal function as defined by:

    °Creatinine clearance ≥ 50 mL/min as calculated using the modified Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) formula OR serum creatinine ≤1.5 x ULN

  • Adequate hepatic function as defined by:

    • AST, ALT, and alkaline phosphatase (ALP) ≤ 3 x ULN with the following exceptions
    • Patients with documented liver metastases: AST, ALT and ALP ≤ 5 x ULN
    • Total bilirubin ≤ 2.0 mg/dL
    • For patients not receiving therapeutic anticoagulation:
    • stable anticoagulant regimen
    • INR ≤ 1.5 x ULN
    • aPTT ≤ 1.5 x ULN
  • Patients with baseline clinical symptoms or laboratory abnormalities that do not meet the definition of dose-limiting toxicity (DLT).
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of DS-3201b or irinotecan, whichever date is later.

    • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • For men of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom with female partners of childbearing potential or pregnant female partners during the treatment period and for at least 6 months after the last dose of DS-3201b or irinotecan, whichever date is later.

    • Men must refrain from donating sperm during this same period as defined above.
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
  • Untreated CNS metastases
  • Patients with treated CNS metastases are allowed on the study as long as their clinical symptoms are adequately controlled and the daily dose of steroid use is equivalent to or less than 10 mg of prednisone.
  • Is receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4/5 within 7 days of first receipt of DS-3201b.

    °Consumption of herbs/fruits that may have an influence on PK of DS-3201b (strong CYP3A inhibitors or inducers) such as St. John's wort, star fruit, Seville orange or Seville orange-containing foods and beverages, grapefruit or grapefruit-containing food or beverages should be avoided from 14 days prior to the start of the study and throughout the entire study.

  • Prior exposure to DS-3201b or other inhibitors of enhancer of zeste homologue-2 (EZH2)
  • Prior exposure to topoisomerase inhibitors, including topotecan and irinotecan

    • Refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, or any other condition that significantly affects gut motility or absorption and would preclude adequate absorption of DS-3201b in the opinion of the treating physician and/or PI.
    • Currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks prior to the initiation of study treatment. Anticancer therapies include chemotherapy, biologics, targeted therapies, immunologics, or other investigational therapy.
  • Currently receiving radiation therapy, or who have received radiation within 2 weeks prior to the initiation of study treatment.
  • Patients who have not recovered to Grade ≤1 or baseline from adverse events due to prior anticancer therapy.
  • Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).

    °NOTE: Procedures such as a percutaneous biopsy, pleural catheter insertion, placement of a central venous catheter or other minor procedures are permitted.

  • QT interval prolongation °Prolongation of corrected QT interval where the mean QTc interval is >450 milliseconds (ms) for men and >470 ms for females or if there are any other additional risk factors for torsade de pointes (i.e. active congestive heart failure or cardiomyopathy with NYHA Grade 3/4 dyspnea, clinically significant cardiac rhythm abnormalities, hypokalemia, family history of Long QT Syndrome). Single EKGs will be obtained at screening and at each pre-specified timepoint as indicated in the table of assessments (Table 3). For any EKG assessment, if the initial EKG shows a prolonged QTc, then two additional EKGs will be obtained and the mean of the 3 EKGs will be used to determine eligibility and for grading of TRAEs.
  • Patients who are currently taking medications that are known to prolong the QT interval and are clearly associated with a known risk of Torsades de Pointes (TdP) even when taken as recommended. Please see Section 11.6 for a full list of excluded medications. Patients who are able to discontinue any prohibited medication prior to the start of study drug at Day -7 will still be considered eligible for the study.
  • Have a known hypersensitivity to any of the components of or known hypersensitivity to either the study drug itself or any of the inactive ingredients in the study drug product.
  • Known liver cirrhosis.
  • Uncontrolled active infection requiring IV antibiotic, antiviral, or anti-fungal medications within 14 days prior to initiation of study treatment.

    °Infections controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per institutional guidelines are acceptable.

  • Congenital or acquired immunodeficiency, including patients with known history or infection with human immunodeficiency virus (HIV).

    °NOTE: HIV-positive patients who are taking anti-retroviral therapy are still ineligible due to potential PK interactions with DS-3201b.

  • Active tuberculosis
  • Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening.

    °Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study.

  • Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening.

    °The HCV RNA test will be performed only for patients who have a positive HCV antibody test.

  • Female patients who have a positive serum pregnancy test during screening or a positive urine pregnancy test on Day 1 before first dose of study drug.
  • Female patients who are lactating and/or plan to breastfeed during the study treatment.

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 ClinicalTrials.gov identifier (NCT number): NCT03879798


Contacts
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Contact: W. Victoria Lai, MD 646-449-1983 laiw@mskcc.org
Contact: Charles Rudin, MD, PhD 646-888-4336

Locations
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United States, New Jersey
Memoral Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: W. Victoria Lai, MD    646-449-1983      
Memoral Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: W. Victoria Lai, MD    646-449-1983      
Memorial Sloan Kettering Bergen Recruiting
Montvale, New Jersey, United States, 07645
Contact: W. Victoria Lai, MD    646-449-1983      
United States, New York
Memorial Sloan Kettering Cancer Commack Recruiting
Commack, New York, United States, 11725
Contact: W. Victoria Lai, MD    646-449-1983      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: W. Victoria Lai, MD    646-449-1983      
Memorioal Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: W. Victoria Lai, MD    646-449-1983      
Contact: Charles Rudin, MD, PhD    646-888-4336      
Memorial Sloan Kettering Nassau Recruiting
Uniondale, New York, United States, 11553
Contact: W. Victoria Lai, MD    646-449-1983      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: W. Victoria Lai, MD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03879798    
Other Study ID Numbers: 18-553
First Posted: March 19, 2019    Key Record Dates
Last Update Posted: March 4, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
Supporting Materials: Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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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 Memorial Sloan Kettering Cancer Center:
DS-3201b
Irinotecan
18-553
Additional relevant MeSH terms:
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Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Irinotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents