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A Study Combining the M3814 Pill With Standard Chemotherapy in Patients With Ovarian Cancer With an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer Patients

NCT04092270

Description:

This phase I trial studies the side effects and best dose of M3814 when given together with pegylated liposomal doxorubicin hydrochloride in treating patients with high or low grade ovarian cancer that has come back (recurrent). M3814 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 M3814 and pegylated liposomal doxorubicin hydrochloride may work better in treating patients with ovarian cancer compared to pegylated liposomal doxorubicin hydrochloride alone.

Related Conditions:
  • Endometrial Endometrioid Adenocarcinoma
  • Fallopian Tube Carcinoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • Fallopian Tube Mucinous Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Low Grade Fallopian Tube Serous Adenocarcinoma
  • Low Grade Ovarian Serous Adenocarcinoma
  • Ovarian Adenocarcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Mucinous Adenocarcinoma
  • Ovarian Seromucinous Carcinoma
  • Ovarian Transitional Cell Carcinoma
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Transitional Cell Carcinoma
  • Primary Peritoneal Undifferentiated Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Combining the M3814 Pill With Standard Chemotherapy in Patients With Ovarian Cancer With an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer Patients
  • Official Title: A Phase I/Ib Dose Escalation Study of Pegylated Liposomal Doxorubicin (PLD) With M3814 in Ovarian Cancer With Planned Expansions in High Grade Serous (HGSOC) and Low Grade Serous Ovarian Cancer (LGSOC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-06123
  • SECONDARY ID: NCI-2019-06123
  • SECONDARY ID: 10324
  • SECONDARY ID: 10324
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT04092270

Conditions

  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • Fallopian Tube Mucinous Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
  • FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
  • FIGO Grade 3 Endometrial Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Seromucinous Carcinoma
  • Ovarian Undifferentiated Carcinoma
  • Platinum-Sensitive Ovarian Carcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Primary Peritoneal Transitional Cell Carcinoma
  • Primary Peritoneal Undifferentiated Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Low Grade Fallopian Tube Serous Adenocarcinoma
  • Recurrent Low Grade Ovarian Serous Adenocarcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Ovarian Clear Cell Adenocarcinoma
  • Recurrent Ovarian Endometrioid Adenocarcinoma
  • Recurrent Ovarian Mucinous Adenocarcinoma
  • Recurrent Ovarian Transitional Cell Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Recurrent Primary Peritoneal Low Grade Serous Adenocarcinoma

Interventions

DrugSynonymsArms
Nedisertib3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814, MSC 2490484A, MSC-2490484A, MSC2490484ATreatment (nedisertib, PLD)
Pegylated Liposomal Doxorubicin HydrochlorideATI-0918, Caelyx, Dox-SL, Doxil, Doxilen, Doxorubicin HCl Liposomal, Doxorubicin HCl Liposome, Doxorubicin Hydrochloride Liposome, Duomeisu, Evacet, LipoDox, Lipodox 50, Liposomal Adriamycin, Liposomal Doxorubicin Hydrochloride, Liposomal-Encapsulated Doxorubicin, Pegylated Doxorubicin HCl Liposome, S-Liposomal Doxorubicin, Stealth Liposomal Doxorubicin, TLC D-99Treatment (nedisertib, PLD)

Purpose

This phase I trial studies the side effects and best dose of M3814 when given together with pegylated liposomal doxorubicin hydrochloride in treating patients with high or low grade ovarian cancer that has come back (recurrent). M3814 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 M3814 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 nedisertib (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 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 nedisertib.

      Patients receive nedisertib orally (PO) twice daily (BID) on days 1-28 and pegylated
      liposomal doxorubicin hydrochloride intravenously (IV) on day 1. Cycles repeat every 28 days
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nedisertib, PLD)ExperimentalPatients receive nedisertib PO BID on days 1-28 and pegylated liposomal doxorubicin hydrochloride IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nedisertib
  • Pegylated Liposomal Doxorubicin Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  DOSE ESCALATION PHASE: Women with recurrent or persistent epithelial ovarian,
             fallopian tube or primary peritoneal cancer are eligible. This includes the following
             histologic types: serous adenocarcinoma (grade 1, 2, or 3/ high grade or low grade),
             endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma,
             clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell
             carcinoma, or adenocarcinoma not otherwise specified

          -  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 or one cycle (whichever is shorter) prior to study
                  treatment initiation

          -  Patients with platinum-sensitive ovarian cancer are eligible for both the dose
             escalation and dose expansion phases if their provider feels that PLD would be an
             appropriate treatment option for them. Patients with platinum-sensitive ovarian cancer
             should also be offered any higher priority studies for which they are potentially
             eligible

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Patients must have a cardiac ejection fraction >= the institutional lower limit of
             normal (LLN)

          -  Hemoglobin >= 9 g/dL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN

          -  Alkaline phosphatase =< 2.5 x institutional ULN

          -  Creatinine =< 1.5 x institutional ULN

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression. The
             patient must be off steroids and clinically stable

          -  Female patients of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study medication.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required

               -  The effects of M3814 and liposomal doxorubicin on the developing human fetus are
                  unknown and there is the potential for teratogenic or abortifacient effects. For
                  this reason, women and men 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 treatment, and for 6 months after
                  completion of M3814 administration. 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. Because there is an unknown but
                  potential risk for adverse events in nursing infants secondary to treatment of
                  the mother with M3814, breastfeeding should be discontinued if the mother is
                  treated with M3814

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

          -  Archival formalin-fixed paraffin-embedded (FFPE) tissue collected within the past 36
             months prior to registration must be available for submission for deoxyribonucleic
             acid (DNA)/ribonucleic acid (RNA) analysis

        Exclusion Criteria:

          -  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 or
             neuropathy

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M3814 or pegylated liposomal doxorubicin

          -  Patients who cannot discontinue concomitant medications or herbal supplements that are
             strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5 and
             CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow therapeutic index are
             also excluded. Patients may confer with the study doctor to determine if alternative
             medications can be used. The following categories of medications and herbal
             supplements must be discontinued for at least the specified period of time before the
             patient can be treated:

               -  Strong inducers of CYP3A4/5 and CYP2C19: >= 3 weeks prior to study treatment

               -  Strong inhibitors of CYP3A4/5 and CYP2C19: >= 1 week prior to study treatment

               -  Substrates of CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study
                  treatment

               -  Because the lists of these agents are constantly changing, it is important to
                  regularly consult a frequently-updated medical reference. 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. Patient Drug Interactions Handout and Wallet Card should be
                  provided to patients

          -  Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors
             (PPIs). Patients may confer with the study doctor to determine if such medications can
             be discontinued. These must be discontinued >= 5 days prior to study treatment.
             Patients do not need to discontinue calcium carbonate

          -  Patients receiving sorivudine or any chemically related analogues (such as brivudine)
             are excluded

          -  Patients who have received a live attenuated vaccine within 30 days of dosing with
             M3814

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because M3814 is DNA-PK inhibitor agent
             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 M3814, breastfeeding should be discontinued if the mother
             is treated with M3814. These potential risks may also apply to other agents used in
             this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description: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 Outcome Measures

Measure:Pharmacokinetics (PK) parameters of nedisertib
Time Frame:Up to 1 year
Safety Issue:
Description:Individual PK parameters will be estimated for maximum of concentration, area under the curve, T1/2, apparent clearance/oral bioavailability, and apparent volume using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters will be reported descriptively for exploratory comparison with historical data. Samples from the expansion phase may also be analyzed for M3814 for the purpose of population-PK analyses.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

June 6, 2020