Gemcitabine Hydrochloride Alone or With M6620 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well ATR kinase inhibitor M6620 (M6620) and gemcitabine hydrochloride work compared to standard treatment with gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of improvement (recurrent). ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking an enzyme needed for cell growth, and may also help gemcitabine hydrochloride work better. Gemcitabine hydrochloride is a drug used in chemotherapy that works to stop the growth of tumor cells by blocking cells from growing and repairing themselves, causing them to die. It is not yet known whether adding ATR kinase inhibitor M6620 to standard treatment with gemcitabine hydrochloride is more effective than gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Assess and compare progression free survival (PFS) between gemcitabine (gemcitabine hydrochloride)/M6620 (VX-970) and gemcitabine alone arms. SECONDARY OBJECTIVES: I. Determine and compare overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. II. Determine and compare the safety profile of gemcitabine/M6620 (VX-970) and gemcitabine alone regimens. III. Assess and compare PFS at 6 months between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. IV. Determine and compare the clinical benefit rate (CBR) between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. V. Determine and compare the duration of response (DOR) between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. VI. Determine and compare cancer antigen (CA)125 reduction by >= 50% between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. VII. Determine and compare overall survival (OS) between gemcitabine/M6620 (VX-970) and gemcitabine alone arms. VIII. Determine the ORR for subjects in the gemcitabine alone arm who cross over to the gemcitabine/M6620 (VX-970) arm. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II. ARM II: Patients receive gemcitabine hydrochloride as in Arm I and ATR kinase inhibitor M6620 IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then every 6 months for 2 years.

Official Title
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Phase 2 Study of M6620 (VX-970) in Combination With Gemcitabine Versus Gemcitabine Alone in Subjects With Platinum-Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer

Conditions
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Ovarian Serous Tumor, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma

Intervention / Treatment
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* Drug: Berzosertib
* Drug: Gemcitabine
* Drug: Gemcitabine Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed high grade serous ovarian or primary peritoneal or fallopian tube cancer; platinum resistant disease is defined as progression within 6 months after last platinum regimen Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; measurable disease by RECIST version (v)1.1 with at least one measurable target lesion Prior therapy: No line limit but no more than 1 prior regimens in the platinum resistant setting; no prior treatment targeting the ATR/checkpoint kinase 1 (CHK1) pathway and no prior gemcitabine as single agent; hormonal therapies immunotherapy, and antiangiogenic therapies (as single agents) do not count as lines; poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP)-inhibitors count as a line of therapy unless given in the maintenance setting; PARP-inhibitors given as maintenance after platinum therapy do not count as a line of therapy; prior carboplatin/gemcitabine is allowed provided that there was no disease progression within 12 months after completion of the carboplatin/gemcitabine regimen; subjects may begin protocol treatment at least 4 weeks or 5 half-lives, whichever is shorter, after their last dose of chemotherapy or hormonal therapy, assuming they are otherwise eligible Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%) Life expectancy of greater than 6 months Leukocytes >= 3,000/mcL (within 2 weeks prior to initiation of study treatment) Absolute neutrophil count >= 1,500/mcL (within 2 weeks prior to initiation of study treatment) Platelets >= 100,000/mcL (within 2 weeks prior to initiation of study treatment) Total bilirubin within normal institutional limits (within 2 weeks prior to initiation of study treatment) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (within 2 weeks prior to initiation of study treatment) Creatinine =< upper limit of institutional normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (within 2 weeks prior to initiation of study treatment) Confirmation of availability of a formalin-fixed, paraffin-embedded (FFPE) tumor specimen with adequate tumor tissue (either one paraffin embedded tissue block OR 10 5-micron unstained slides from the block on regular [non-plus] slides and 1 hematoxylin and eosin [H&E] slide) All acute, clinically significant treatment-related toxicity from prior therapy, except for alopecia, must have resolved to grade =< 1 prior to study entry At least 4 weeks since major surgery or radiation therapy The effects of M6620 (VX-970) on the developing human fetus are unknown; for this reason and because deoxyribonucleic acid (DNA) damage inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of study; 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 No known hypersensitivity or contraindication to the components of study treatment (M6620 [VX-970], gemcitabine) Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with primary platinum refractory disease, defined as progression while first line platinum based chemotherapy Patients who have had chemotherapy within 4 weeks or five half-lives, whichever is shorter, (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients who have had radiotherapy within 4 weeks Patients who are receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; a scan to confirm the absence of brain metastasis is not required History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX-970) or gemcitabine M6620 (VX-970) is primarily metabolized by CYP3A4; therefore concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450 3A (CYP3A4 enzyme) are ineligible; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because M6620 (VX-970) and/or gemcitabine are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M6620 (VX-970) and/or gemcitabine, breastfeeding should be discontinued if the mother is treated with M6620 (VX-970) and/or gemcitabine Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with M6620 (VX-970) and/or gemcitabine; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (gemcitabine hydrochloride)<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II. | Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;|
| Experimental: Arm II (gemcitabine, ATR kinase inhibitor M6620)<br>Patients receive gemcitabine hydrochloride as in Arm I and ATR kinase inhibitor M6620 IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Berzosertib<br>* Given IV<br>* Other names: VX970;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was summarized using Kaplan-Meier analyses and compared between the two arms using the logrank test. Additionally, PFS was analyzed using a Cox Proportional Hazards Model, including the stratification factor, and will be used to estimate the hazard ratio of the gemcitabine hydrochloride (gemcitabine)/ataxia telangiectasia mutated and Rad3-related (ATR) kinase inhibitor M6620 (formerly VX-970) arm relative to the gemcitabine alone arm and the associated 90% confidence interval. Disease progression, per protocol, is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the diameters of target lesions, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Number of days from the day the subject received the first dose of protocol therapy to the date of documented progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death (regardless of cause), assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Defined as the percentage of subjects achieving a response rating of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in the whole population. Per RECIST v1.1 definitions for target lesions and assessed by conventional CT and MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the diameters of target lesions; Overall Response (OR) = CR + PR. ORR was summarized by counts (percentages) in each Arm. | Up to 3 years | 
| Progression Free Survival at 6 Months (PFS-6) | Assessed and compared PFS-6 between gemcitabine/VX-970 and gemcitabine alone arms | Number of days from the day the subject received the first dose of protocol therapy to the date of documented progressive disease by RECIST version 1.1 or death (regardless of cause), assessed at 6 months | 
| Clinical Benefit Rate (CBR) | CBR is defined as the percentage of subjects achieving a response rating of stable disease >= 4 months, partial response (PR), or complete response (CR). Subject demographic and baseline characteristics will be summarized by mean, standard deviation, median, minimum, and maximum for continuous variables; and by counts and percentages for categorical variables. Summaries will be provided separately for each treatment group. Treatment group comparisons in CBR will be evaluated using logistic regression and expressed as odds ratios with associated 90% confidence intervals. In the event that rates are low, comparisons will be based on Fisher's exact test. | Up to 3 years | 
| Objective Response Rate by Platinum Free Status | Objective response rate by platinum-free status includes only informational summaries (counts of participants who met the categories outlined below) without formal statistical comparisons. | Up to 3 years | 
| Percentage of Patients With a Reduction in CA-125 | Determined and compared CA125 reduction by > 50% between gemcitabine/VX-970 and gemcitabine alone arms. | CA-125 serum samples were collected from participants in both Arms I and II at baseline, on Day 1 of each cycle, and at the end-of-study treatment visit, assessed up to 2 years. | 
| Overall Survival (OS) | Assessed and compared OS between gemcitabine/VX-970 and gemcitabine alone arms. | Number of weeks from the date of registration until date of death (regardless of cause), assessed up to 3 years. | 
| Number of Participants With Serious Adverse Events (SAEs) | Determined and compared the safety profile of gemcitabine/VX-970 and gemcitabine alone regimens. | AE checks occurred on D1 and D8 of each cycle for up to 2 years and at the Final Treatment Visit. Patients who were removed from study treatment for unacceptable AEs were followed until resolution/stabilization of the AE up to 3 years, or until death. | 
| Duration of Response | Duration of response was evaluated at the first instance of CR or PR through the earliest assessment of progressive disease, death, or the last follow-up where the subject had not yet progressed from her prior response. Informational summaries without formal statistical comparisons were produced. | Assessed for up to 3 years. |