Description:
This phase I trial studies the side effects and best dose of gemcitabine hydrochloride and
berzosertib when given together with carboplatin in treating patients with ovarian, primary
peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other
places in the body (metastatic). Chemotherapy drugs, such as carboplatin and gemcitabine
hydrochloride, work in different ways to stop the growth of tumor cells, either by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Berzosertib
may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Giving berzosertib with chemotherapy (carboplatin and gemcitabine hydrochloride) may work
better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer
compared to chemotherapy alone.
Title
- Brief Title: Carboplatin, Gemcitabine Hydrochloride, and Berzosertib in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
- Official Title: Phase 1 Dose Escalation and Expansion Cohort of Carboplatin and Gemcitabine With or Without M6620 (VX-970) in First or Second Recurrence Platinum-Sensitive Epithelial Ovarian, Peritoneal, and Fallopian Tube Cancer
Clinical Trial IDs
- ORG STUDY ID:
NCI-2015-02064
- SECONDARY ID:
NCI-2015-02064
- SECONDARY ID:
MC1563
- SECONDARY ID:
9948
- SECONDARY ID:
9948
- SECONDARY ID:
N01CM00099
- SECONDARY ID:
P30CA015083
- SECONDARY ID:
UM1CA186686
- SECONDARY ID:
UM1CA186709
- NCT ID:
NCT02627443
Conditions
- High Grade Ovarian Serous Adenocarcinoma
- Metastatic Fallopian Tube Carcinoma
- Metastatic Ovarian Carcinoma
- Metastatic Primary Peritoneal Carcinoma
- Ovarian Endometrioid Tumor
- Platinum-Sensitive Ovarian Carcinoma
- Recurrent Fallopian Tube Carcinoma
- Recurrent Ovarian Carcinoma
- Recurrent Primary Peritoneal Carcinoma
- Stage IV Fallopian Tube Cancer AJCC v6 and v7
- Stage IV Ovarian Cancer AJCC v6 and v7
- Stage IV Primary Peritoneal Cancer AJCC v7
Interventions
Drug | Synonyms | Arms |
---|
Berzosertib | 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970 | Treatment (carboplatin, gemcitabine hydrochloride, VX-970) |
Carboplatin | Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo | Treatment (carboplatin, gemcitabine hydrochloride, VX-970) |
Gemcitabine Hydrochloride | dFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011 | Treatment (carboplatin, gemcitabine hydrochloride, VX-970) |
Purpose
This phase I trial studies the side effects and best dose of gemcitabine hydrochloride and
berzosertib when given together with carboplatin in treating patients with ovarian, primary
peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other
places in the body (metastatic). Chemotherapy drugs, such as carboplatin and gemcitabine
hydrochloride, work in different ways to stop the growth of tumor cells, either by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Berzosertib
may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Giving berzosertib with chemotherapy (carboplatin and gemcitabine hydrochloride) may work
better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer
compared to chemotherapy alone.
Detailed Description
PRIMARY OBJECTIVES:
I. Assess safety and tolerability of the combination therapy carboplatin, gemcitabine
hydrochloride (gemcitabine), and berzosertib (M6620 [VX-970]) in adult women with platinum
sensitive recurrent high grade serous or high grade endometrioid ovarian, primary peritoneal
or fallopian tube cancer. (Phase I Dose Escalation/Safety Lead-in) II. Determine the dose of
the triple therapy to be used in the dose expansion cohort of the study. (Phase I Dose
Escalation/Safety Lead-in) III. Confirm the safety at the maximum tolerated dose (MTD) for
the addition of M6620 (VX-970) to carboplatin and gemcitabine in first or second recurrence
of platinum sensitive high grade serous or endometrioid ovarian, primary peritoneal or
fallopian tube carcinoma. (Expansion Cohort)
SECONDARY OBJECTIVES:
I. To determine if the MTD for the combination of carboplatin, gemcitabine and M6620 (VX-970)
improves the confirmed response rate in adult women with platinum sensitive recurrent high
grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian tube cancer.
II. To determine the impact of the MTD on overall survival (OS), duration of response, and
progression-free survival (PFS).
INTEGRATED CORRELATIVE STUDY OBJECTIVES:
I. Collection of specimens for biomarker studies to provide preliminary proof of mechanism.
Assess, in an exploratory fashion, whether the combination of gemcitabine and carboplatin
activates the ATR/CHK1 pathway at achievable concentrations and also whether M6620 inhibits
the activated pathway.
II. To determine whether increased deoxyribonucleic acid (DNA) damage as assessed by two
different multiplex assays correlates with response to combination therapy with M6620
(VX-970).
III. To determine whether mutations in homologous recombination repair genes correlate with
response to combination therapy with M6620 (VX-970).
IV. To ascertain modulation of ATR autophosphorylation and other pharmacodynamic readouts for
ATR inhibition by M6620 (VX-970).
OUTLINE: This is a dose-escalation study of gemcitabine hydrochloride and berzosertib.
Patients receive carboplatin intravenously (IV) over 30 minutes on day 1, gemcitabine
hydrochloride IV over 30 minutes on days 1 and 8, and berzosertib IV over 60 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 for 3 years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (carboplatin, gemcitabine hydrochloride, VX-970) | Experimental | Patients receive carboplatin IV over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and berzosertib IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | - Berzosertib
- Carboplatin
- Gemcitabine Hydrochloride
|
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or
fallopian tube malignancy that is metastatic and for which curative measures do not
exist. The histology can be confirmed from tissue that was taken at the time of
diagnosis. A biopsy at the time of recurrence prior to enrollment on study is not
required
- 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
- Patients enrolled in the expansion cohort will be required to have archival tumor
tissue available for analysis and be willing to have a tumor biopsy at baseline (after
registration and prior to starting study treatment), at cycle 1 day 2 and at cycle 2
day 2. Patients must have platinum sensitive disease and be in their first or second
platinum sensitive recurrence. Platinum sensitive disease is defined as recurrence
that occurred greater than six months after completion of their last line of platinum
based therapy. No non-platinum regimens allowed; prior therapy with PARP inhibitors as
well as bevacizumab is allowed
- No more than two prior platinum based regimens. One regimen is defined as the interval
of treatment from start of platinum based doublet to finish of that treatment course
for the initial therapy or for the recurrent disease episode. If the nonplatinum agent
is altered due to any reason other than disease progression, it counts as one regimen.
For example, if a patient started on carboplatin and paclitaxel but developed a taxol
reaction and was switched to carboplatin and Abraxane, this counts as one prior
regimen
- Children are excluded from this study, but will be eligible for future pediatric
trials
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 6 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2 x institutional upper limit of normal (ULN)
- Creatinine within normal institutional limits OR creatinine clearance >= 50
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Negative serum pregnancy test result for females of child bearing potential
- Note: The effects of M6620 (VX-970) on the developing human fetus are unknown.
For this reason and because deoxyribonucleic acid (DNA)-damage response (DDR)
inhibitors as well as other therapeutic agents used in this trial may have
teratogenic potential, 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 M6620 (VX-970) administration. Should a woman become pregnant or
suspect she is pregnant while she is participating in this study, she should
inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients with platinum resistant disease or platinum sensitive disease that is past
the first or second recurrence
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier, excluding alopecia. Patients with treatment
related effects, such as peripheral neuropathy, that are grade 1 or less are eligible
- Prior exposure to gemcitabine
- 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
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M6620 (VX-970), carboplatin, gemcitabine or to these specific compounds
- 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. 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) as a DNA-damage
response (DDR) inhibitor may have 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), breastfeeding should
be discontinued if the mother is treated with M6620 (VX-970). These potential risks
also apply to the other agents used in this study, such as carboplatin and gemcitabine
- Patients with Li Fraumeni syndrome are excluded from the study as M6620 (VX-970) is a
DDR inhibitor
- Addition of bevacizumab to the treatment in this study is not allowed; if the treating
physician feels that the addition of bevacizumab is in the best interest of the
patient, the patient should be treated with an FDA approved regimen outside of the
present study
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose (MTD) (phase I dose escalation) |
Time Frame: | Up to 28 days |
Safety Issue: | |
Description: | The MTD in this study will be defined as the highest safely tolerated dose, up to a maximum of dose level 4, where at most 1 out of six patients experience a dose limiting toxicity (DLT) with the next higher dose having at least 2 DLTs in 3 or more patients. Will be reported descriptively. |
Secondary Outcome Measures
Measure: | Confirmed response rate |
Time Frame: | Up to 3 years |
Safety Issue: | |
Description: | Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. |
Measure: | Overall survival (OS) |
Time Frame: | From study entry to death from any cause, assessed up to 3 years |
Safety Issue: | |
Description: | OS will be estimated using the Kaplan-Meier method. |
Measure: | Duration of response |
Time Frame: | From first documented date of confirmed response (complete response [CR] or partial response [PR]), to the date at which progression is first documented, up to 3 years |
Safety Issue: | |
Description: | The duration of confirmed responses will be assessed using the Kaplan-Meier method. |
Measure: | Progression free survival (PFS) |
Time Frame: | From registration to the first of either disease progression or death from any cause, up to 3 years |
Safety Issue: | |
Description: | Disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 19, 2021