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

Solid Tumors Clinical Trial

Official title:

Randomized Phase II Trial of Topotecan Plus M6620 (VX-970) vs. Topotecan Alone in Patients With Relapsed Small-Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04162041
• Other study ID #: 200009
• Secondary ID: 20-C-0009
• Status: Recruiting
• Phase: Phase 2
• Start date: November 20, 2019
• Est. completion date: December 1, 2022

Study information

• Verified date: November 12, 2019
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Rasa Vilimas, R.N.
• Phone: (240) 858-3158
• Email: rasa.vilimas[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: December 1, 2022
• Est. primary completion date: June 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• ELIGIBILITY 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

OR

--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.

Related Conditions & MeSH terms

• Carcinoma, Small Cell
• Extrapulmonary Lung Cancer
• Lung Neoplasms
• Relapse
• SCLC
• Small Cell Lung Carcinoma
• Solid Tumors

Intervention

Drug:
• Topotecan + M6620
Participants meeting inclusion and exclusion criteria will receive either monotherapy with topotecan 1.25 mg /m2 IV Days 1-5 or combination therapy consisting of topotecan 1.25 mg /m2 IV Days 1-5 with M6620 210 mg/m2 IV Days 2 and 5 administered each 21 day cycle until disease progression or development of intolerable side effects.
• Topotecan
Participants meeting inclusion and exclusion criteria will receive either monotherapy with topotecan 1.25 mg /m2 IV Days 1-5 or combination therapy consisting of topotecan 1.25 mg /m2 IV Days 1-5 with M6620 210 mg/m2 IV Days 2 and 5 administered each 21-day cycle until disease progression or development of intolerable side effects.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	progression-free survival (PFS)	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)	Disease progression

External Links

•   NIH Clinical Center Detailed Web Page