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

NCT ID: NCT02595892

Last Updated: 2025-08-26

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-25
• Study Completion Date: 2026-08-05

Brief Summary

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

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.

Conditions

Ovarian Serous Tumor; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (gemcitabine hydrochloride)

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.

Group Type: ACTIVE_COMPARATOR

Gemcitabine

Intervention Type: DRUG

Given IV

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Arm II (gemcitabine, ATR kinase inhibitor M6620)

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.

Group Type: EXPERIMENTAL

Berzosertib

Intervention Type: DRUG

Given IV

Gemcitabine

Intervention Type: DRUG

Given IV

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Interventions

Berzosertib

Given IV

Intervention Type: DRUG

Gemcitabine

Given IV

Intervention Type: DRUG

Gemcitabine Hydrochloride

Given IV

Intervention Type: DRUG

Other Intervention Names

2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-; M 6620; M6620; VX 970; VX-970; VX970; dFdC; dFdCyd; Difluorodeoxycytidine; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; Gemzar; LY 188011; LY-188011; LY188011

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Panagiotis A Konstantinopoulos

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber - Harvard Cancer Center LAO

Locations

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, United States

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

UC San Diego Medical Center - Hillcrest

San Diego, California, United States

Mayo Clinic in Florida

Jacksonville, Florida, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, United States

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

M D Anderson Cancer Center

Houston, Texas, United States

University of Virginia Cancer Center

Charlottesville, Virginia, United States

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, United States

Countries

United States

References

Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, Penson RT, Schumer ST, Doyle LA, Lee EK, Kohn EC, Duska LR, Crispens MA, Olawaiye AB, Winer IS, Barroilhet LM, Fu S, McHale MT, Schilder RJ, Farkkila A, Chowdhury D, Curtis J, Quinn RS, Bowes B, D'Andrea AD, Shapiro GI, Matulonis UA. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jul;21(7):957-968. doi: 10.1016/S1470-2045(20)30180-7. Epub 2020 Jun 15.

Reference Type: DERIVED

PMID: 32553118 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2015-01910

Identifier Type: REGISTRY

Identifier Source: secondary_id

16-724

Identifier Type: -

Identifier Source: secondary_id

9944

Identifier Type: OTHER

Identifier Source: secondary_id

9944

Identifier Type: OTHER

Identifier Source: secondary_id

UM1CA186709

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2015-01910

Identifier Type: -

Identifier Source: org_study_id