Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers

NCT02487095 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15015015-C-0150
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Chemotherapy damages cancer cell deoxyribonucleic acid (DNA) so the cells die, and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy. Objective: To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer. Eligibility: Adults at least 18 years old with small cell lung cancer. Design: Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study. The study is set in 21-day cycles. Participants will get topotecan intravenous (IV) on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2. Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that. For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect. More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1. Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit. A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.

Conditions

Carcinoma, Non-Small -Cell Lung; Ovarian Neoplasms; Small Cell Lung Carcinoma; Uterine Cervical Neoplasms; Carcinoma, Neuroendocrine; Extrapulmonary Small Cell Cancer

Keywords

RB1 Inactivation; Kinase Inhibitor; DNA Damage Response Network; MYC And CCNE1 Activation; Defective ATM-p53 Signaling Pathway

Outcome Measures

Primary Outcomes (4)

• Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan

  MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for \>7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.

  End of Cycle 1, approximately 3 weeks

• Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620)

  MTD is defined as the dose level at which no more than 1 of 6 subjects experience a dose-limiting toxicity (DLT) during one cycle of treatment. A DLT is defined using the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 and is related or possibly drug related, such as neutropenia Grade 4 for \>7 days duration, febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection), or Grade 3 thrombocytopenia. Death due to drug related adverse events.

  End of Cycle 1, approximately 3 weeks

• Ph II: Number of Participants With a Clinical Response

  Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

  Every two cycles (each cycle is 21 days) up to approximately 30 months.

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  Date treatment consent signed to date off study, approximately 9 months and 9 days for Ph I DL1, 42 months and 12 days for Ph I DL2, 15 months and 9 days for Ph I DL3, 17 months and 9 days for Ph I DL4, and 43 months and 22 days for Ph II DL4.

Secondary Outcomes (9)

• Phase I: Progression-free Survival (PFS)

  At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months

• Phase II: Progression-free Survival (PFS)

  At disease progression, an average of 3.28 months.

• Phase I and Phase II: Duration of Response (DOR)

  At disease progression, an average of 5.25 months.

• Phase I: Overall Survival (OS)

  On-study date until date of death, an average of 17.65 months.

• Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment)

  Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3

Other Outcomes (1)

• Phase I Number of Participants With a Dose Limiting Toxicity (DLT)

  End of Cycle 1, approximately 3 weeks

Study Arms (2)

1/Phase I VX-970 (M6620) + topotecan

EXPERIMENTAL

VX-970 (M6620) + topotecan at escalating doses

Drug: Topotecan; Drug: VX-970 (M6620)

2/Phase II VX-970 (M6620) + topotecan

EXPERIMENTAL

VX-970 (M6620) + topotecan at maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D)

Drug: Topotecan; Drug: VX-970 (M6620)

Interventions

Topotecan DRUG

Topotecan (in combination with VX-970 (M6620) administered by intravenous (IV) Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Also known as: Hycamtin

1/Phase I VX-970 (M6620) + topotecan; 2/Phase II VX-970 (M6620) + topotecan

VX-970 (M6620) DRUG

VX-970 (M6620 (in combination with Topotecan) administered by intravenous (IV) Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Also known as: M6620

1/Phase I VX-970 (M6620) + topotecan; 2/Phase II VX-970 (M6620) + topotecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Both Phase I and Phase II:
• Male and female subjects greater than or equal to 18 years of age. Because no dosing adverse event data are currently available on the use of topotecan in combination with VX-970 (M6620) in subjects less than 18 years of age, children are excluded from this study, but will be eligible for future pediatrics trials.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Subjects with evaluable, but not measurable disease will be eligible for Phase 1.
• Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.
• Adequate organ functions
• Hemoglobin greater than or equal to 9.0 g/dL
• Absolute neutrophil count greater than or equal to 1.5x10\^9/L
• Platelets greater than or equal to 100x10\^9/L
• Total Bilirubin less than or equal to 2.0 mg/dL
• Transaminases less than or equal to 2 x upper limit of normal (ULN) or if liver metastases were present, less than or equal to 3xULN
• Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula greater than or equal to 60 mL/min
• Ability of subject to understand and the willingness to sign a written informed consent document.
• The effects of VX-970 (M6620) on the developing human fetus are unknown For this reason and because topotecan is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study participation and for 6 months after the last dose study therapy. 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.
• Phase I:

You may not qualify if:

• Subjects with tumor amenable to potentially curative therapy.
• Subjects who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
• Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
• Subjects requiring any medications or substances that are strong inhibitors or inducers of cytochrome p450, family 3, subfamily A (CYP3A) during the course of the study are ineligible. Lists including strong inhibitors and inducers of cytochrome p450 3A4 (CYP3A4) are provided.
• Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
• Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with VX-970 (M6620). In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• Pregnant women are excluded from this study because topotecan is a Class D agent with the potential for teratogenic or abortifacient effects and because the effects of VX-970 (M6620) on the developing human fetus are currently unknown. In addition, because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with topotecan or VX-970 (M6620), breastfeeding should be discontinued if the mother is treated with these agents.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier JD, Furey B, Golec J, Reaper PM, Pollard JR. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014 Jul 30;5(14):5674-85. doi: 10.18632/oncotarget.2158.

  PMID: 25010037 BACKGROUND

• Josse R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79. doi: 10.1158/0008-5472.CAN-13-3369. Epub 2014 Sep 30.

  PMID: 25269479 BACKGROUND

• Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, Hanrahan AJ, Scott SN, Brannon AR, McDermott GC, Pirun M, Ostrovnaya I, Kim P, Socci ND, Viale A, Schwartz GK, Reuter V, Bochner BH, Rosenberg JE, Bajorin DF, Berger MF, Petrini JH, Solit DB, Taylor BS. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov. 2014 Sep;4(9):1014-21. doi: 10.1158/2159-8290.CD-14-0380. Epub 2014 Jun 16.

  PMID: 24934408 BACKGROUND

• Thomas A, Redon CE, Sciuto L, Padiernos E, Ji J, Lee MJ, Yuno A, Lee S, Zhang Y, Tran L, Yutzy W, Rajan A, Guha U, Chen H, Hassan R, Alewine CC, Szabo E, Bates SE, Kinders RJ, Steinberg SM, Doroshow JH, Aladjem MI, Trepel JB, Pommier Y. Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol. 2018 Jun 1;36(16):1594-1602. doi: 10.1200/JCO.2017.76.6915. Epub 2017 Dec 18.

  PMID: 29252124 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Ovarian Neoplasms; Small Cell Lung Carcinoma; Uterine Cervical Neoplasms; Carcinoma, Neuroendocrine

Interventions

Topotecan; berzosertib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Uterine Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Anish Thomas
• Organization: National Cancer Institute

thomasa6@nih.gov

240-760-7343

Study Officials

• Anish Thomas, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 27, 2015
• First Posted: July 1, 2015
• Study Start: July 30, 2015
• Primary Completion: February 24, 2021
• Study Completion: December 26, 2024
• Last Updated: April 13, 2025
• Results First Posted: April 12, 2022

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)