A Phase I/Ib Dose Escalation Study of Pegylated Liposomal Doxorubicin (PLD) With Peposertib (M3814) in Platinum - Resistant or Ineligible Ovarian and Related Cancers With Planned Expansions in High Grade Serous (HGSOC) and Low Grade Serous Ovarian Cancer (LGSOC)
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Enrollment
- 54
- Locations
- 22
- Primary Endpoint
- Incidence of adverse events
Overview
Brief Summary
This phase I trial studies the side effects and best dose of peposertib when given together with pegylated liposomal doxorubicin hydrochloride in treating patients with high or low grade ovarian cancer that has come back after a period of improvement (recurrent). Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin 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. Giving peposertib and pegylated liposomal doxorubicin hydrochloride may work better in treating patients with ovarian cancer compared to pegylated liposomal doxorubicin hydrochloride alone.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of peposertib (M3814) in combination with pegylated liposomal doxorubicin hydrochloride (PLD) and determine the recommended phase 2 dose (RP2D) of the combination in women with recurrent ovarian cancer.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetics of peposertib (M3814) when given in combination with PLD.
EXPLORATORY OBJECTIVE:
I. To correlate response to treatment (as defined by response rate and progression free survival) with PLD exposure (in area under the curve [AUC]) and PLD associated toxicities in women with recurrent high grade serous and low grade serous ovarian cancer treated in the expansion cohorts.
OUTLINE: This is a dose-escalation study of peposertib followed by a dose-expansion study.
Patients receive peposertib orally (PO) twice daily (BID) on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) during screening and every 8 weeks throughout the study and after 6 months of study treatment, every 12 weeks. Patients undergo echocardiography (ECHO) during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or multigated acquisition (MUGA) scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
After completion of study treatment, patients are followed up for 30 days.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •DOSE ESCALATION PHASE: Women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer are eligible. This includes, but is not limited to, the following histologic types: serous adenocarcinoma (grade 1,2, or 3/ high grade or low grade), endometrioid adenocarcinoma, carcinosarcoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, or adenocarcinoma not otherwise specified
- •NOTE: Patients who have evidence of DDR deficiency /HRD are eligible if they are at the point in their disease course where they are appropriate candidates for single agent Doxil
- •EXPANSION PHASE: The expansion phase will simultaneously accrue to 2 cohorts, low grade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC)
- •Patients accrued to the LGSOC cohort will have recurrent or persistent low grade serous ovarian cancer or grade 1 serous ovarian cancer
- •Patients accrued to the HGSOC cohort will have recurrent or persistent high grade serous ovarian cancer
- •Patients must have measurable disease by defined Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- •Prior therapy:
- •Patients must have received at least one prior line of platinum-based chemotherapy
- •Patients can have received an unlimited number of additional lines of chemotherapy, targeted therapy, biologic therapy, or hormonal therapy
- •Any prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted therapy, immunotherapy, or hormonal therapy must be discontinued at least 4 weeks, one cycle, or 5 half-lives (whichever is shortest) prior to study treatment initiation
Exclusion Criteria
- •Patients are excluded from the dose-escalation phase of the study if they are eligible for any available therapies known to confer clinical benefit
- •Inability to swallow and/or absorb oral medication (patients with a drainage peg are ineligible)
- •Patients may not have received prior anthracyclines (doxorubicin or pegylated liposomal doxorubicin) for treatment of their ovarian cancer
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia, thyroid dysfunction, or neuropathy
- •Patients who are receiving any other investigational agents within 28 days prior to start of treatment
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to peposertib (M3814) or pegylated liposomal doxorubicin
- •Patients who cannot discontinue concomitant medications or herbal supplements that potentially interact with peposertib (M3814)
- •The following categories of medications and herbal supplements must be discontinued prior to starting study treatment:
- •Strong inducers/inhibitors of CYP3A4/5, CYP2C9, and CYP2C19
- •Substrates with a narrow therapeutic index that are metabolized by CYP1A2, 2B6, 2C8, and 3A4/5
Arms & Interventions
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Computed Tomography (Procedure)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Echocardiography Test (Procedure)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Biospecimen Collection (Procedure)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Multigated Acquisition Scan (Procedure)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Peposertib (Drug)
Treatment (peposertib, PLD)
Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles. Additionally, patients undergo blood sample collection throughout the study.
Intervention: Pegylated Liposomal Doxorubicin Hydrochloride (Drug)
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 3 years
The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for adverse event reporting.
Secondary Outcomes
- Pharmacokinetics (PK) parameters of nedisertib(Up to 3 years)