Phase 2
N=21
Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers
Carcinoma, Non-Small -Cell Lung · Ovarian Neoplasms · Small Cell Lung Carcinoma · Uterine Cervical Neoplasms · Carcinoma, Neuroendocrine
Bottom Line
View on ClinicalTrials.gov: NCT02487095 ↗Enrolled (actual)
21
Serious AEs
64.5%
Results posted
Apr 2022
Primary outcome: Primary: Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan — 1.25 mg/m^2
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Topotecan (Drug); VX-970 (M6620) (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Feb 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan |
1.25 | — |
| PRIMARY Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620) |
210 | — |
| PRIMARY Ph II: Number of Participants With a Clinical Response |
0; 0; 9; 3; 2; 6 | — |
| PRIMARY Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) |
6; 6; 3; 6; 41 | — |
| SECONDARY Phase I: Progression-free Survival (PFS) |
1.38; 7.88; 1.15; 5.025 | — |
| SECONDARY Phase II: Progression-free Survival (PFS) |
4.6; 2.2 | — |
| SECONDARY Phase I and Phase II: Duration of Response (DOR) |
NA; NA; NA; NA; 4.9; 5.6 | — |
| SECONDARY Phase I: Overall Survival (OS) |
5.125; 10.1; 3.844; 9.1 | — |
| SECONDARY Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) |
4; 4; 3; 5; 5; 4 | — |
| SECONDARY Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Peripheral Blood Mononuclear Cells (PBMCs) From Baseline (Day 1 Pre-Treatment) |
5; 2; 3; 3; 6; 6 | — |
| SECONDARY Percentage of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 14 (CD14)+ Monocytes Among Viable Cells, and Regulatory T Cells Among Cluster of Differentiation 4 (CD4)+ T Cells At Baseline and Post-Treatment |
33.30; 35.4; 38.20; 22.50; 34.25; 31.50 | — |
| SECONDARY Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment |
0.55; 1.12; 0.86; 1.10; 0.63; 0.64 | — |
| SECONDARY Phase II: Overall Survival (OS) |
6.5 | — |
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.
Eligibility Criteria
- INCLUSION CRITERIA:
- 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:
- Subjects with histologically confirmed small-cell lung cancer (SCLC), non- small cell lung cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of diagnosis will be done at National Cancer Institute (NCI) Laboratory of Pathology. Patients with other histologies will be allowed if no standard treatment options exist.
- At least one prior chemotherapy
- NSCLC subjects with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations should have previously received appropriate Food and Drug Administration (FDA) approved therapies in addition to prior chemotherapy
- Phase II:
- Histological confirmation of SCLC, or extrapulmonary small cell cancer. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist.
- Subjects with both platinum-sensitive and platinum-refractory disease will be eligible
EXCLUSION CRITERIA
- 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, inc
Data sourced from ClinicalTrials.gov (NCT02487095). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.