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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

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ClinicalTrials.gov Identifier: NCT04092270
Recruitment Status : Recruiting
First Posted : September 17, 2019
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Nedisertib Drug: Pegylated Liposomal Doxorubicin Hydrochloride Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 24, 2020
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : September 1, 2022


Arm Intervention/treatment
Experimental: Treatment (nedisertib, PLD)
Patients 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.
Drug: Nedisertib
Given PO
Other Names:
  • 3-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
  • MSC2490484A

Drug: Pegylated Liposomal Doxorubicin Hydrochloride
Given IV
Other Names:
  • ATI-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-99




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 1 year ]
    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 :
  1. Pharmacokinetics (PK) parameters of nedisertib [ Time Frame: Up to 1 year ]
    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.


Other Outcome Measures:
  1. Tumor response [ Time Frame: Within the first 10 months of treatment ]
    Tumor response will be defined according to Response Evaluation Criteria in Solid Tumors 1.1 and refers to the best overall response occurring.

  2. Duration of response [ Time Frame: From response documentation until progression of disease, assessed up to 1 year ]
  3. Progression-free survival [ Time Frame: From the beginning of the treatment until the progression date, death date, or the last radiological assessment without progressive disease, assessed up to 1 year ]
    Will be estimated using Kaplan-Meier method.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04092270


Locations
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United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Site Public Contact    434-243-6303    PAS9E@virginia.edu   
Principal Investigator: Linda R. Duska         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rachel N Grisham JHU Sidney Kimmel Comprehensive Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04092270    
Other Study ID Numbers: NCI-2019-06123
NCI-2019-06123 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10324 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10324 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: September 17, 2019    Key Record Dates
Last Update Posted: May 5, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Adenocarcinoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Carcinoma, Transitional Cell
Cystadenocarcinoma, Serous
Carcinoma, Endometrioid
Adenocarcinoma, Mucinous
Cystadenocarcinoma
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Cystic, Mucinous, and Serous
Endometrial Neoplasms
Uterine Neoplasms
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors