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

Study Overview
=================
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.

Official Title
-----------------
A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers

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

Intervention / Treatment
-----------------
* Drug: Topotecan
* Drug: VX-970 (M6620)


Participation Criteria
=================
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, 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase I VX-970 (M6620) + topotecan<br>VX-970 (M6620) + topotecan at escalating doses | Drug: Topotecan<br>* 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.<br>* Other names: Hycamtin;Drug: VX-970 (M6620)<br>* 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.<br>* Other names: M6620;|
| Experimental: 2/Phase II VX-970 (M6620) + topotecan<br>VX-970 (M6620) + topotecan at maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) | Drug: Topotecan<br>* 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.<br>* Other names: Hycamtin;Drug: VX-970 (M6620)<br>* 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.<br>* Other names: M6620;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | At disease progression | 
| 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). | At disease progression, an average of 3.28 months. | 
| 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. | At disease progression, an average of 5.25 months. | 
| Phase I and Phase II: Overall Survival (OS) | OS is defined as the time from the on-study date until date of death or last follow-up. | On-study date until date of death, an average of 6.95 months. | 
| 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. | Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3 | 
| 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. | Day 1 Pre-Treatment, Post treatment on day 2, and Post treatment on day 3 | 
| 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. | Baseline and 3 weeks post-treatment | 
| 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. | Baseline and 3 weeks post-treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RB1 Inactivation, Kinase Inhibitor, DNA Damage Response Network, MYC And CCNE1 Activation, Defective ATM-p53 Signaling Pathway