Carcinoma, Neuroendocrine, Carcinoma, Non-Small -Cell Lung, Extrapulmonary Small Cell Cancer, Ovarian Neoplasms, Small Cell Lung Carcinoma, Uterine Cervical Neoplasms
Conditions
Keywords
RB1 Inactivation, Kinase Inhibitor, DNA Damage Response Network, MYC And CCNE1 Activation, Defective ATM-p53 Signaling Pathway
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.
Detailed description
Background: Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and becomes refractory to treatment within a few months. There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand deoxyribonucleic acid (DNA) breaks leading to lethal double-strand DNA breaks. The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests the existence of a highly effective DNA damage response network. SCLC is characterized by high replication stress (RB transcriptional corepressor 1 (RB1) inactivation, MYC and cyclin E1 (CCNE1) activation) and defective ataxia-telangiectasia mutated tumor protein p53 (ATM-p53) signaling pathway, which cause an excessive reliance on ataxia-telangiectasia rad 3-related (ATR) for survival following DNA damage. We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as topotecan will provide an attractive synthetically lethal therapeutic option for SCLC. VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents. Primary objectives: Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with VX-970. Phase 2: To assess the efficacy with respect to clinical response rate of a combination of topotecan and VX-970 in the second-line treatment of patients with SCLC. Eligibility: Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment. Phase 1: Subjects with histologically confirmed SCLC, non-small cell cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histologies will be allowed if no standard treatment options exist. Patients with evaluable, but not measurable disease will be eligible for Phase I. Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be eligible. Patients must have measurable disease to be eligible for Phase II. Design: Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 administered every 21 days (1 cycle), until disease progression or development of intolerable side effects. Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment on day 1, post treatment on days 2, and 3) for pharmacodynamic (PD) analyses. Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease progression except for subjects at the first dose level. Participants at the first dose level will undergo biopsies on day 3 prior to third dose of topotecan. Participants will be monitored weekly during the first cycle by clinic visit and basic labs. Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Follow-up for survival will be carried out every 3 months.
Interventions
DRUGTopotecan
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.
DRUGVX-970 (M6620)
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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, 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 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. | 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. |
| Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan | End of Cycle 1, approximately 3 weeks | 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. |
| Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620) | End of Cycle 1, approximately 3 weeks | 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. |
| Ph II: Number of Participants With a Clinical Response | Every two cycles (each cycle is 21 days) up to approximately 30 months. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3 | 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. |
| 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 | Baseline and 3 weeks post-treatment | 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. |
| Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline and 3 weeks post-treatment | Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD8/CD4 T cell ratio. |
| Phase II: Progression-free Survival (PFS) | At disease progression, an average of 3.28 months. | 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). |
| Phase I: Progression-free Survival (PFS) | At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months | 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). |
| Phase II: Overall Survival (OS) | On-study date until date of death, an average of 12.22 months. | OS is defined as the time from the on-study date until date of death or last follow-up. |
| Phase I and Phase II: Duration of Response (DOR) | At disease progression, an average of 5.25 months. | 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. |
| Phase I: Overall Survival (OS) | On-study date until date of death, an average of 17.65 months. | OS is defined as the time from the on-study date until date of death or last follow-up. |
| 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase I Number of Participants With a Dose Limiting Toxicity (DLT) | End of Cycle 1, approximately 3 weeks | 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Phase I DL1 Topotecan 1mg/m^2 Intravenous (IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 5 Phase I Dose Level (DL) 1 Topotecan 1mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 140mg/m\^2 IV on day 5 | 6 |
| Phase I DL2 Topotecan 1mg/m^2 Intravenous (IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 Phase I Dose Level (DL) 2 Topotecan 1mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 140mg/m\^2 IV on day 2, 5 | 6 |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 Phase I Dose Level (DL) 3 Topotecan 1.25mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 140mg/m\^2 IV on day 2, 5 | 3 |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 Phase I Dose Level (DL) 4 Topotecan 1.25mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 210mg/m\^2 IV on day 2, 5 | 6 |
| Phase II DL4 Topotecan 1.25mg/m^2 VX970 (M6620) 210mg/m^2 Recommended Phase II Dose Phase I Dose Level (DL) 4 Topotecan 1.25mg/m\^2 intravenous (IV) (days 1-5); VX970 (M6620) 210mg/m\^2 IV on day 2, 5 Maximum Tolerated Dose/Recommended Phase II Dose
26 participants with small cell lung cancer (SCLC) and 15 with extrapulmonary small cell cancer (EPSCC) are included in this Arm/Group. | 41 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Expansion | Unable to scan/restage participant | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase I DL2 Topotecan 1mg/m^2 Intravenous (IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Total | Phase I DL1 Topotecan 1mg/m^2 Intravenous (IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 5 | Phase II DL4 Topotecan 1.25mg/m^2 VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 15 Participants | 0 Participants | 13 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 47 Participants | 6 Participants | 28 Participants | 5 Participants | 3 Participants |
| Age, Continuous | 56.75 years STANDARD_DEVIATION 15.43 | 59.16 years STANDARD_DEVIATION 11.27 | 57.98 years STANDARD_DEVIATION 4.75 | 59.67 years STANDARD_DEVIATION 12.3 | 60.27 years STANDARD_DEVIATION 5.73 | 57.17 years STANDARD_DEVIATION 8.81 |
| Eastern Cooperative Oncology Group (ECOG) 0 | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) 1 | 6 Participants | 59 Participants | 6 Participants | 38 Participants | 6 Participants | 3 Participants |
| Eastern Cooperative Oncology Group (ECOG) 2 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 58 Participants | 5 Participants | 38 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Number of Participants That Received Prior Therapy | 6 Participants | 62 Participants | 6 Participants | 41 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 54 Participants | 6 Participants | 35 Participants | 6 Participants | 3 Participants |
| Region of Enrollment United States | 6 participants | 62 participants | 6 participants | 41 participants | 6 participants | 3 participants |
| Sex: Female, Male Female | 3 Participants | 38 Participants | 3 Participants | 26 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 24 Participants | 3 Participants | 15 Participants | 3 Participants | 0 Participants |
| Tumor Type Cervical carcinoma | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Cervical small-cell carcinoma | 0 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants |
| Tumor Type Endometrial cancer | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Mesothelioma | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Tumor Type Non-small cell lung cancer | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Non-small cell lung cancer transformed to Small cell lung cancer | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Tumor Type Ovarian cancer | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Pancreatic cancer | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Rectal high-grade neuroendocrine carcinomas (HGNEC) | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Small cell bladder cancer | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Tumor Type Small cell bladder vs prostate (tumor type undefined) | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Small cell breast cancer | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Tumor Type Small-cell carcinoma | 1 Participants | 31 Participants | 1 Participants | 26 Participants | 3 Participants | 0 Participants |
| Tumor Type Small cell gallbladder | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Small cell ovarian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Small cell prostate cancer | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Small cell rectal | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Thymoma | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 6 / 6 | 3 / 3 | 5 / 6 | 35 / 41 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 3 / 3 | 6 / 6 | 41 / 41 |
| serious Total, serious adverse events | 3 / 6 | 4 / 6 | 3 / 3 | 5 / 6 | 25 / 41 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 6 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 6 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 3 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 6 Participants |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 41 Participants |
Primary
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.
Time frame: Every two cycles (each cycle is 21 days) up to approximately 30 months.
Population: 1/26 participants was not evaluable for response in the Phase II DL4 SCLC group. Phase II, DL4 Arm/Group is split into two groups for this outcome measure because the distinction is relevant for the phase II, DL4 since extrapulmonary small cell cancers (EPSCC) was an exploratory cohort of the phase II DL4 (added with an amendment).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Ph II: Number of Participants With a Clinical Response | Complete Response | 0 Participants |
| All Participants | Ph II: Number of Participants With a Clinical Response | Partial Response | 9 Participants |
| All Participants | Ph II: Number of Participants With a Clinical Response | Progressive Disease | 2 Participants |
| All Participants | Ph II: Number of Participants With a Clinical Response | Stable Disease | 14 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ph II: Number of Participants With a Clinical Response | Stable Disease | 6 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ph II: Number of Participants With a Clinical Response | Complete Response | 0 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ph II: Number of Participants With a Clinical Response | Progressive Disease | 6 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ph II: Number of Participants With a Clinical Response | Partial Response | 3 Participants |
Primary
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.
Time frame: End of Cycle 1, approximately 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Topotecan | 1.25 mg/m^2 |
Primary
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.
Time frame: End of Cycle 1, approximately 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Ph I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of VX-970 (M6620) | 210 mg/m^2 |
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
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.
Time frame: Baseline and 3 weeks post-treatment
Population: Only one participant had a post treatment sample in phase 1 DL3.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | 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 | Baseline CD14+ monocytes among viable cells | 33.30 percentage of PBMCs |
| All Participants | 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 | Post-Treatment CD14+ monocytes among viable cells | 31.50 percentage of PBMCs |
| All Participants | 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 | Baseline regulatory T cells among CD4+ T cells | 3.19 percentage of PBMCs |
| All Participants | 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 | Post-Treatment regulatory T cells among CD4+ T cells | 1.87 percentage of PBMCs |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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 | Baseline CD14+ monocytes among viable cells | 35.4 percentage of PBMCs |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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 | Post-Treatment regulatory T cells among CD4+ T cells | 4.42 percentage of PBMCs |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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 | Post-Treatment CD14+ monocytes among viable cells | 34.95 percentage of PBMCs |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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 | Baseline regulatory T cells among CD4+ T cells | 3.80 percentage of PBMCs |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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 | Post-Treatment regulatory T cells among CD4+ T cells | 1.79 percentage of PBMCs |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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 | Post-Treatment CD14+ monocytes among viable cells | 23.70 percentage of PBMCs |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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 | Baseline regulatory T cells among CD4+ T cells | 3.32 percentage of PBMCs |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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 | Baseline CD14+ monocytes among viable cells | 38.20 percentage of PBMCs |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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 | Baseline CD14+ monocytes among viable cells | 22.50 percentage of PBMCs |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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 | Post-Treatment CD14+ monocytes among viable cells | 33.25 percentage of PBMCs |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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 | Post-Treatment regulatory T cells among CD4+ T cells | 3.11 percentage of PBMCs |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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 | Baseline regulatory T cells among CD4+ T cells | 3.92 percentage of PBMCs |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | 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 | Post-Treatment regulatory T cells among CD4+ T cells | 2.53 percentage of PBMCs |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | 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 | Baseline regulatory T cells among CD4+ T cells | 3.50 percentage of PBMCs |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | 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 | Post-Treatment CD14+ monocytes among viable cells | 32.75 percentage of PBMCs |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | 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 | Baseline CD14+ monocytes among viable cells | 34.25 percentage of PBMCs |
Secondary
Phase I and Phase II: Duration of Response (DOR)
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.
Time frame: At disease progression, an average of 5.25 months.
Population: 1/26 participants were not evaluable in the Phase II DL4 SCLC group. The Phase II, DL4 Arm/Group is split into two groups for this outcome measure because the distinction is relevant for the phase II, DL4 since extrapulmonary small cell cancers (EPSCC) was an exploratory cohort of the phase II DL4 (added with an amendment). Only 1 participant was evaluable in Phase 1 DL1 and Phase 1 DL4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Phase I and Phase II: Duration of Response (DOR) | NA Months |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I and Phase II: Duration of Response (DOR) | NA Months |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I and Phase II: Duration of Response (DOR) | NA Months |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I and Phase II: Duration of Response (DOR) | NA Months |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | Phase I and Phase II: Duration of Response (DOR) | 4.9 Months |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I and Phase II: Duration of Response (DOR) | 5.6 Months |
Secondary
Phase II: Overall Survival (OS)
OS is defined as the time from the on-study date until date of death or last follow-up.
Time frame: On-study date until date of death, an average of 12.22 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Phase II: Overall Survival (OS) | 6.5 Months |
Secondary
Phase II: Progression-free Survival (PFS)
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).
Time frame: At disease progression, an average of 3.28 months.
Population: The Phase II, DL4 Arm/Group is split into two groups for this outcome measure because the distinction is relevant for the phase II, DL4 since extrapulmonary small cell cancers (EPSCC) was an exploratory cohort of the phase II DL4 (added with an amendment).1/26 participants was not evaluable for response in the Phase II DL4 SCLC group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Phase II: Progression-free Survival (PFS) | 4.6 Months |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase II: Progression-free Survival (PFS) | 2.2 Months |
Secondary
Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment)
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.
Time frame: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
Population: 17/21 participants were analyzed in Phase I DL1 because these 17 patients had good quality hair samples (plucked hairs with good hair bulbs).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 2 | 4 Participants |
| All Participants | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 3 | 5 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 3 | 4 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 2 | 4 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 2 | 3 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 3 | 3 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 2 | 5 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I: Number of Participants With a Change in H2AX Phosphorylation (ƴH2AX) Levels in Hairs From Baseline (Day 1 Pre-Treatment) | Post treatment on day 3 | 5 Participants |
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)
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.
Time frame: Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | 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) | Post treatment on day 2 | 5 Participants |
| All Participants | 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) | Post treatment on day 3 | 6 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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) | Post treatment on day 3 | 6 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | 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) | Post treatment on day 2 | 2 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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) | Post treatment on day 2 | 3 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | 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) | Post treatment on day 3 | 2 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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) | Post treatment on day 2 | 3 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | 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) | Post treatment on day 3 | 3 Participants |
Secondary
Phase I: Overall Survival (OS)
OS is defined as the time from the on-study date until date of death or last follow-up.
Time frame: On-study date until date of death, an average of 17.65 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Phase I: Overall Survival (OS) | 5.125 Months |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I: Overall Survival (OS) | 10.1 Months |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I: Overall Survival (OS) | 3.844 Months |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I: Overall Survival (OS) | 9.1 Months |
Secondary
Phase I: Progression-free Survival (PFS)
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).
Time frame: At disease progression - 0.68 months to 88.27 months, an Average Mean of 10.6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Phase I: Progression-free Survival (PFS) | 1.38 Months |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I: Progression-free Survival (PFS) | 7.88 Months |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I: Progression-free Survival (PFS) | 1.15 Months |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I: Progression-free Survival (PFS) | 5.025 Months |
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
Blood samples were collected via venipuncture and immunophenotyping of PBMCs were performed by multiparameter flow cytometry for CD8/CD4 T cell ratio.
Time frame: Baseline and 3 weeks post-treatment
Population: Only one participant had a post treatment sample in phase 1 DL3.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Post treatment CD8/CD4 T cell ratio | 0.64 Ratio |
| All Participants | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline CD8/CD4 T cell ratio | 0.55 Ratio |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Post treatment CD8/CD4 T cell ratio | 1.11 Ratio |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline CD8/CD4 T cell ratio | 1.12 Ratio |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline CD8/CD4 T cell ratio | 0.86 Ratio |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Post treatment CD8/CD4 T cell ratio | 0.29 Ratio |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline CD8/CD4 T cell ratio | 1.10 Ratio |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Post treatment CD8/CD4 T cell ratio | 0.99 Ratio |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Post treatment CD8/CD4 T cell ratio | 0.58 Ratio |
| Phase II Dose Level (DL) 4 Topotecan 1.25mg/m^2; VX970 (M6620) 210mg/m^2 Recommended Phase II Dose | Ratio of Peripheral Blood Mononuclear Cells (PBMCs): Cluster of Differentiation 8 (CD8)/Cluster of Differentiation 4 (CD4) T Cells at Baseline and Post-Treatment | Baseline CD8/CD4 T cell ratio | 0.63 Ratio |
Other Pre-specified
Phase I Number of Participants With a Dose Limiting Toxicity (DLT)
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.
Time frame: End of Cycle 1, approximately 3 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Phase I Number of Participants With a Dose Limiting Toxicity (DLT) | 1 Participants |
| Phase II DL 4 - Extrapulmonary Small Cell Cancer (EPSCC)Topotecan 1.25mg/m^2 IV/VX970 210mg/m^2 IV | Phase I Number of Participants With a Dose Limiting Toxicity (DLT) | 1 Participants |
| Phase I DL3 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 140mg/m^2 IV on Day 2, 5 | Phase I Number of Participants With a Dose Limiting Toxicity (DLT) | 0 Participants |
| Phase I DL4 Topotecan 1.25mg/m^2 Intravenous(IV) (Days 1-5); VX970 (M6620) 210mg/m^2 IV on Day 2, 5 | Phase I Number of Participants With a Dose Limiting Toxicity (DLT) | 1 Participants |