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

NCT02595892 | Active Not Recruiting Phase 2 Results

• 4 other identifiers: NCI-2015-0191016-7249944UM1CA186709
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 17

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Objective Response Rate (ORR)

  Up to 3 years

• Progression Free Survival at 6 Months (PFS-6)

  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)

  Up to 3 years

• Objective Response Rate by Platinum Free Status

  Up to 3 years

• Percentage of Patients With a Reduction in CA-125

  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.

Study Arms (2)

Arm I (gemcitabine hydrochloride)

ACTIVE COMPARATOR

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; Drug: Gemcitabine Hydrochloride

Arm II (gemcitabine, ATR kinase inhibitor M6620)

EXPERIMENTAL

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; Drug: Gemcitabine; Drug: Gemcitabine Hydrochloride

Interventions

Gemcitabine Hydrochloride DRUG

Given IV

Also known as: dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemcitabine HCI, Gemzar, LY 188011, LY-188011, LY188011

Arm I (gemcitabine hydrochloride); Arm II (gemcitabine, ATR kinase inhibitor M6620)

Berzosertib DRUG

Given IV

Also known as: 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970

Arm II (gemcitabine, ATR kinase inhibitor M6620)

Gemcitabine DRUG

Given IV

Also known as: dFdC, dFdCyd, Difluorodeoxycytidine

Arm I (gemcitabine hydrochloride); Arm II (gemcitabine, ATR kinase inhibitor M6620)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (17)

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

UC San Diego Medical Center - Hillcrest

San Diego, California, 92103, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• 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.

  PMID: 32553118 DERIVED

MeSH Terms

Conditions

Fallopian Tube Neoplasms; Ovarian Neoplasms

Interventions

berzosertib; Gemcitabine

Condition Hierarchy (Ancestors)

Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Panagiotis Konstantinopoulos, MD, PhD
• Organization: Dana-Farber Cancer Institute

panagiotis_konstantinopoulos@dfci.harvard.edu

617-632-5269

Study Officials

• Panagiotis A Konstantinopoulos

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2015
• First Posted: November 4, 2015
• Study Start: August 25, 2016
• Primary Completion: June 15, 2020
• Study Completion (Estimated): August 5, 2026
• Last Updated: April 13, 2026
• Results First Posted: October 25, 2022

Record last verified: 2026-02

Locations

US (17)