Trial Outcomes & Findings for Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers (NCT NCT02487095)

No participants were treated on Dose Level -1, Topotecan 1mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 105mg/m\^2 IV on day 5.

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

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.

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.

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.

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.

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as 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).

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as 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).

DOR is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented in response to the combination in both platinum sensitive and refractory patients. CR is disappearance of all non-target lesions and normalization of tumor marker level. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

OS is defined as the time from the on-study date until date of death or last follow-up.

Hair samples were obtained from participants to determine a change in H2AX phosphorylation (named ƴH2AX) in the hair follicles when compared to baseline (day 1 pre-treatment). ƴH2AX signals were detected by immunochemistry (microscopy) by using an antibody specific against ƴH2AX that, in turn, was detected by a secondary antibody conjugated to a fluorescent probe. ƴH2AX signal intensity was measured in bottom of hair bulbs. A change is defined as change in ƴH2AX signal (fluorescence intensity) in cells located toward the top of the hair bulbs.

PBMCs were obtained from participants to determine a change in H2AX phosphorylation (named ƴH2AX) in peripheral blood mononuclear cells (PBMCs) when compared to baseline (day 1 pre-treatment). ƴH2AX was detected by immunochemistry (microscopy) by using an antibody specific against ƴH2AX that, in turn, was detected by a secondary antibody conjugated to a fluorescent probe. Changes in ƴH2AX levels in PBMCs is defined as changes in numbers of ƴH2AX foci per cells.

Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD14+ monocytes among viable cells, and regulatory T cells among CD4+ T cells.

Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD8/CD4 T cell ratio.

OS is defined as the time from the on-study date until date of death or last follow-up.

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.