Topotecan Plus M6620 (VX-970) vs. Topotecan Alone in People With Relapsed Small-Cell Lung Cancer

  • STATUS
    Recruiting
  • End date
    Dec 1, 2022
  • participants needed
    12
  • sponsor
    National Cancer Institute (NCI)
Updated on 18 November 2019
topotecan

Summary

Background

Small cell cancers are aggressive and grow fast. They can appear in the lungs and in other parts of the body. These tumors often don t respond well to treatment if they come back after chemotherapy. Treatment with two drugs combined may be able to help.

Objective

To compare M6620 plus topotecan to topotecan alone in people with small cell lung cancer (SCLC). Also, to test the effects of M6620 plus topotecan in people with small cell cancer outside the lungs.

Eligibility

People ages 18 and older with relapsed SCLC or small cell cancer outside the lungs

Design

Participants will be screened with:

Physical exam

Blood and heart tests

CT scan

Tumor biopsy: This is mandatory for participants with SCLC. It is optional for those with small cell cancer outside the lungs.

Participants with SCLC will be randomly assigned to 1 of 2 groups: to receive either M6620 and topotecan or topotecan alone. Outside of the lungs small cell cancer participants will be assigned to receive both drugs.

Participants will receive treatment in 21-day cycles. They will get topotecan through a vein in the arm on days 1 5 of each cycle. Some participants also will receive M6620 through a vein in the arm on days 2 and 5 of each cycle.

Participants will have blood tests and physical exams every cycle. They will have CT scans every 6 weeks.

Participants will continue treatment as long as their cancer does not get worse and they can handle the side effects.

After treatment, participants will have visits every 3 months. Visits will include blood tests and CT scans.

Patients randomized 2:1 ie 2 times more likely to get the combination vs. single drug

Patients who receive single drug may receive the combination at the time of progression

Description

Background
  • SCLC is the most aggressive and lethal form of lung cancer. It represents 15% of all lung cancers, with an annual incidence of over 34,000 cases in the United States alone.
  • Relapsed SCLC has been traditionally classified into sensitive and resistant disease according to the type of response to first-line therapy and to treatment-free interval.
  • Topotecan is Food and Drug Administration (FDA)-approved for patients with SCLC with chemotherapy-sensitive disease after failure of first-line chemotherapy (platinum and etoposide).
  • Topotecan inhibits re-ligation of topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand DNA breaks (DSB).
  • We showed that inhibition of ATR by short interfering RNA or VE-821 and its clinical derivative M6620 sensitizes tumor cells to TOP1 inhibitors.
  • We found that a combination of an Ataxia telangiectasia and Rad3-related (ATR) inhibitor and topotecan can be safely combined and that heightening replicative stress in this manner can yield durable responses in small cell cancers and initiated a Phase 1/2 trial of the

combination.

  • In this current study, we hypothesize that the combination of M6620 and topotecan can improve progression free survival (PFS) compared with topotecan alone in patients with relapsed SCLC.
  • In the recently reported phase I clinical trial, we defined a safe and effective dose of topotecan plus M6820. The proposed randomized phase II trial is based on promising preliminary efficacy data seen in SCLC patients treated on phase I and the ongoing phase II trials.
    Objectives

-To determine if the combination of M6620 with topotecan will result in an improvement in progression-free survival (PFS) compared to topotecan alone in patients with relapsed small cell lung cancer (SCLC).

Eligibility

-Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at diagnosis, with extensive disease at study entry with measurable disease at random assignment per RECIST 1.1. Both platinum-sensitive and platinum-resistant patients will

be included.

  • Patients must be greater than or equal to18 years of age
  • Patients who have received prior topotecan therapy are not eligible.
  • Patients who are receiving any other investigational agents, and with uncontrolled intercurrent illness are not eligible.
    Design
  • This study is an open label, randomized phase 2 study of patients with relapsed SCLC.
  • SCLC patients who have failed prior therapy will be randomized 2:1 to receive either topotecan in combination with M6620 or topotecan alone.
  • Patients will be stratified at the time of randomization for being sensitive or resistant/refractory to prior therapy.
  • Patients on the topotecan monotherapy arm will be eligible to cross-over to receive the combination treatment at progression.
  • It is expected that approximately 25-30 patients per year (about 2-3 patients per month) can be accrued onto the randomized portion of this trial, and thus accrual will be completed in approximately 2 years.
  • A separate cohort of 20 patients with extrapulmonary small cell cancer will be accrued while the primary cohort is accruing and will only receive the combination therapy.
  • This is planned as a multicenter study through CTEP. NCI CCR will be the lead and coordinating site

Details
Condition Oat cell carcinoma, Relapse, Small Cell Lung Cancer, Solid Tumors, Extrapulmonary Lung Cancer
Treatment Topotecan, Topotecan + M6620
Clinical Study IdentifierNCT04162041
SponsorNational Cancer Institute (NCI)
Last Modified on18 November 2019

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at diagnosis, with relapse at study entry with measurable disease at random assignment per RECIST 1.1. See Section 12 for the evaluation of measurable disease. Both platinumsensitive and platinum-resistant patients will be included
Patients with extrapulmonary small cell cancers (cancers with small cell morphology and arising outside the lung, such as small cell prostate, bladder, etc; see Sections 2.1 and 2.2 for disease description and rationale.) will be eligible for the exploratory cohort
Patients must be greater than or equal to 18 years of age because no dosing or adverse event data are currently available on the use of M6620 in combination with topotecan in patients <18 years of age
ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%)
Patients must have adequate organ and marrow function as defined below
Hemoglobin greater than or equal to 9.0 g/dL - patients may receive transfusion to meet the Hb eligibility
Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mcL
Platelets greater than or equal to 100,000/mcL
Total Bilirubin less than or equal to 2 mg/dL
AST(SGOT)/ALT(SGPT) less than or equal to 3.0 (SqrRoot) institutional ULN
Creatinine less than or equal to institutional ULN
-Glomerular Filtration Rate (GFR) greater than or equal to 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73m2
Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are eligible as long as they are on effective anti-retroviral therapy with undetectable viral load within 6 months and there is no drug-drug interaction with M6220
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
The effects of M6620 on the developing human fetus are unknown. For this reason and because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completion of M6620 administration. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after completion of M6620 administration
Patients with treated brain metastases are eligible if they are symptomatically stable while off steroid therapy for a minimum of 21 days
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients with symptomatic brain metastasis are not eligible due to their extremely poor prognosis and since it is unclear whether the investigational agent penetrates the blood brain barrier. However, subjects who have had treatment for their brain metastasis and
are symptomatically stable while off steroid therapy for a minimum of 21 days may be enrolled
Patients who have received prior topotecan therapy
Patients who have had chemotherapy or radiotherapy within 3 weeks prior to enrolment
Patients who have not recovered from adverse events due to prior anti-cancer therapy except hair loss and peripheral neuropathy (i.e., have residual toxicities > Grade 1)
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 or topotecan used in study
M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, HCV and HIV protease inhibitors, nefazodone, posaconazole, telithromycin, voriconazole) or
inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John s Wort) should be avoided. Patients requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or of which to minimize use. The Patient Drug Interactions Handout and Wallet Card should be provided to patients. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Patients with uncontrolled intercurrent illness
Pregnant women are excluded from this study because M6620 as a DDR inhibitor may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the
mother with M6620, breastfeeding should be discontinued if the mother is treated with M6620. These potential risks may also apply to topotecan used in this study
Patients with high grade neuroendocrine cancers, but with no small cell morphology will not be eligible
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Patients with Li-Fraumeni syndrome will not be eligible
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