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Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma and Other Solid Tumors

Primary Purpose

Malignant Solid Neoplasm, NUT Carcinoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Abemaciclib
BET Bromodomain Inhibitor ZEN-3694
Biopsy
Biospecimen Collection
Diagnostic Imaging
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Solid Neoplasm

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • Dose Escalation Cohort Only: Participants must have evaluable disease or measurable disease per RECIST 1.1 criteria
  • Dose Expansion Cohort Only:

    • Participants must have a diagnosis of NUT carcinoma (NC) based on standard criteria for the disease, with diagnostic testing performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory:

      • Ectopic expression of NUT protein (> 50% tumor nuclei) as determined by immunohistochemistry (IHC) testing, OR
      • Detection of the NUT gene translocation as determined by fluorescence in situ hybridization (FISH) testing
    • Participants must have measurable disease per RECIST 1.1 criteria
  • Any number of prior lines of therapy in the metastatic setting are allowed, including prior BET inhibitor therapy and prior CDK4/6 inhibitor therapy
  • Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy. A washout period of at least 21 days is required between last chemotherapy dose (provided the patient did not receive radiotherapy)
  • Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy
  • Participants may have previously undergone surgical resection
  • Age >= 12 years. Patients 12-17 years of age must be > 40 kg at enrollment. Patients 12-17 years of age will not participate in the mandatory tumor biopsies. Since there is no data on patients less than 18 years of age, this population may require lower doses and additional safety precautions and should be closely monitored
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 for participants >= 16 years of age, Lansky >= 50% if < 16 years of age
  • Hemoglobin >= 8 g/dL; Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 1 x 10^11/L
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) for age. Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN for age
  • Serum or plasma creatinine =< 1.5 x institutional ULN OR calculated creatinine clearance >= 50 mL/min (via the chronic kidney disease epidemiology (CKD-EPI) glomerular filtration rate estimation for participants >= 18 years old, or Schwartz formula for participants 12 - 17 years old)
  • 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 and has been clinically stable for at least 1 month. Patients must meet the following criteria:

    • Disease outside the CNS is present
    • Recovery from acute toxicity associated with the treatment to =< CTCAE grade 1 or baseline (with the exception of alopecia), with no requirement for escalating doses of corticosteroids over the past 7 days
  • 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 should be New York Heart Association Functional Classification of class 2B or better
  • Ability to swallow and retain oral medications
  • The effects of ZEN00364 and abemaciclib on the developing human fetus are unknown. For this reason and because BETi and CDKi-inhibiting agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women of child-bearing potential must have a negative pregnancy test prior to study entry. 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. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 weeks after completion of ZEN003694 and abemaciclib administration

    • For female subjects of child-bearing potentially receiving ZEN003694, hormonal means of birth control alone, such as oral, injectable, dermal, subdermal or topical contraceptives are NOT acceptable forms of birth control given that their efficacy has not been evaluated when given in combination with the investigational drugs. "Adequate contraception" is defined as the following:

      • Contraceptive methods with a failure rate of =< 1% used in combination with the barrier method. The following contraceptive methods are acceptable to use in combination with the barrier method: intrauterine device (IUD), intrauterine system (IUS), or oral contraceptive pills (OCPs) that meet the < 1% failure rate as stated in the product label. Note: Hormonal IUDs/OCPs may only be used if the following criteria are met: male condoms are required AND subjects are informed of the potential for reduced systemic hormone levels from the IUD/OCP when taking ZEN003694. Alternatively, male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records
    • Male subjects with female partners of child-bearing potential must use one of the following contraceptive methods:

      • Vasectomy with documentation of azoospermia OR
      • Condom use PLUS partner use of a highly effective contraceptive (=< 1% rate of failure per year) such as intrauterine device or system, or hormonal birth control such as contraceptive subdermal implant, combined estrogen and progestogen oral contraceptive, injectable progestogen, contraceptive vaginal ring, or percutaneous contraceptive patches
    • Male subjects should not donate sperm while on study and for 12 weeks after the last dose of study medication. Male subjects whose partners are or become pregnant must continue to use condoms for 12 weeks after the last dose of study medication
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available may be eligible after discussion with the Principal Investigator of this study. There will be a separate assent process for minors

Exclusion Criteria:

  • Participants who have had cytotoxic chemotherapy, immunotherapy, or other investigational therapy within 2 weeks prior to entering the study. There is a two week required washout period for previous BET inhibitor therapy
  • Participants who have had radiotherapy within at least 2 weeks prior to entering the study. Stereotactic radiosurgery (SRS) within 1 week prior to entering the study will be allowed
  • Participants who have had major surgery within 3 weeks prior to entering the study
  • Participants who have received tyrosine kinase inhibitors (TKIs) or small molecules within 5 half-lives or 1 week (whichever is shorter) of study entry
  • Patients who are receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or abemaciclib
  • Patients requiring medications or substances that are strong inhibitors or strong inducers of CYP3A4 or CYP3A enzymes are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 and abemaciclib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 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
  • Patients with uncontrolled intercurrent illness, including but not limited to: ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance < 30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea that, in the judgment of the investigator, would preclude participation in this study
  • Pregnant women are excluded from this study because ZEN003694 is a BETi 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 ZEN003694, breastfeeding should be discontinued if the mother is treated with ZEN003694. These potential risks may also apply to other agents used in this study
  • Fridericia's correction formula (QTcF) >= 450 msec on screening electrocardiogram (ECG)
  • Patients receiving any medications or substances that are Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) or Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
  • Patients with radiation to > 25% of the bone marrow
  • Patients who have had a bone-targeted radionuclide within 6 weeks of the first dose of ZEN003694
  • Myocardial infarction or unstable angina within 6 months prior to the first dose of ZEN003694
  • Impairment of gastrointestinal function that may significantly alter the absorption of ZEN003694 and/or abemaciclib
  • The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest

Sites / Locations

  • Dana-Farber Cancer InstituteRecruiting
  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ZEN003694, abemaciclib)

Arm Description

Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off, and abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study.

Outcomes

Primary Outcome Measures

Maximum tolerated dose or recommended phase 2 dose (Phase I dose escalation)
The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0 criteria.
Incidence of adverse events (Phase I dose expansion)
Safety will be reported with descriptive statistics. Toxicity will be graded according to National Cancer Institute CTCAE, v5.0. Toxicities will be summarized by maximum grade and by treatment arm. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.
Overall response rate (Phase I dose expansion)
Will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.
Clinical benefit rate (CBR) (Phase I dose expansion)
Clinical benefit is defined as CR, PR or SD >= 24 weeks according to Response Evaluation Criteria in Solid Tumors 1.1. CBR will be reported with 90% exact confidence intervals.
Duration of response (DoR) (Phase I dose expansion)
Median DOR will be reported with ranges.
Time to response (TTR) (Phase I dose expansion)
Median DOR will be reported with ranges.
Overall survival (Phase I dose expansion)
Progression free survival (Phase I dose expansion)

Secondary Outcome Measures

Pharmacokinetics (PK)
Designed the PK sampling to enable simultaneous estimation of individual pharmacokinetic parameters of abemaciclib, ZEN003694, and their respective metabolites using nonlinear mixed effects modeling. Will compare the ratio of observed/historical 90% confidence interval of abemaciclib exposure.
Thymidine kinase (TK)
Will compare exposures of abemaciclib and abemaciclib metabolites to TK activity at cycle 1 day 15 and beyond and also change in TK activity versus clinical outcomes.

Full Information

First Posted
May 12, 2022
Last Updated
September 28, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05372640
Brief Title
Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma and Other Solid Tumors
Official Title
A Phase 1 Study of BET Bromodomain Inhibitor ZEN003694 in Combination With the CDK4/6 Inhibitor Abemaciclib in Patients With NUT Carcinoma and Other Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 29, 2023 (Anticipated)
Primary Completion Date
June 1, 2025 (Anticipated)
Study Completion Date
June 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I trial tests the safety, side effects, and best dose of a ZEN003694 when given together with abemaciclib in treating patients with NUT carcinoma or other solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that overproduce BET protein. Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ZEN003694 and abemaciclib may help shrink or stabilize cancer in patients with NUT carcinoma or other solid tumors.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of BET bromodomain inhibitor ZEN-3694 (ZEN003694) and abemaciclib. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Determine the preliminary rates of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to response (TTR) and duration of response (DoR) for the combination of ZEN003694 and abemaciclib in participants utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. III. Evaluate the pharmacokinetic (PK) profile of the combination. EXPLORATORY OBJECTIVE: I. Explore potential biomarker indicators of response and resistance in tumor tissue and blood samples. OUTLINE: This is a dose-escalation study of BET bromodomain inhibitor ZEN-3694 followed by a dose expansion study. Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 or 5 days on and 2 days off, and abemaciclib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study. After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, and then every 6 months for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Solid Neoplasm, NUT Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ZEN003694, abemaciclib)
Arm Type
Experimental
Arm Description
Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off, and abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study.
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Other Intervention Name(s)
LY-2835219, LY2835219, Verzenio
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
BET Bromodomain Inhibitor ZEN-3694
Other Intervention Name(s)
BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo biopsy
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo blood sample collection
Intervention Type
Procedure
Intervention Name(s)
Diagnostic Imaging
Other Intervention Name(s)
Medical Imaging
Intervention Description
Undergo imaging evaluation
Primary Outcome Measure Information:
Title
Maximum tolerated dose or recommended phase 2 dose (Phase I dose escalation)
Description
The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0 criteria.
Time Frame
During the first cycle of therapy (28 days)
Title
Incidence of adverse events (Phase I dose expansion)
Description
Safety will be reported with descriptive statistics. Toxicity will be graded according to National Cancer Institute CTCAE, v5.0. Toxicities will be summarized by maximum grade and by treatment arm. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.
Time Frame
Up to 5 years
Title
Overall response rate (Phase I dose expansion)
Description
Will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.
Time Frame
Up to 5 years
Title
Clinical benefit rate (CBR) (Phase I dose expansion)
Description
Clinical benefit is defined as CR, PR or SD >= 24 weeks according to Response Evaluation Criteria in Solid Tumors 1.1. CBR will be reported with 90% exact confidence intervals.
Time Frame
Up to 5 years
Title
Duration of response (DoR) (Phase I dose expansion)
Description
Median DOR will be reported with ranges.
Time Frame
From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years
Title
Time to response (TTR) (Phase I dose expansion)
Description
Median DOR will be reported with ranges.
Time Frame
From the time initiation of therapy to the time measurement criteria are met for CR or PR (whichever is first recorded), assessed up to 5 years
Title
Overall survival (Phase I dose expansion)
Time Frame
From study enrollment until death due to any cause, assessed up to 5 years
Title
Progression free survival (Phase I dose expansion)
Time Frame
From study enrollment until the identification of disease progression or death, assessed up to 5 years
Secondary Outcome Measure Information:
Title
Pharmacokinetics (PK)
Description
Designed the PK sampling to enable simultaneous estimation of individual pharmacokinetic parameters of abemaciclib, ZEN003694, and their respective metabolites using nonlinear mixed effects modeling. Will compare the ratio of observed/historical 90% confidence interval of abemaciclib exposure.
Time Frame
Up to 5 years
Title
Thymidine kinase (TK)
Description
Will compare exposures of abemaciclib and abemaciclib metabolites to TK activity at cycle 1 day 15 and beyond and also change in TK activity versus clinical outcomes.
Time Frame
Up to 5 years
Other Pre-specified Outcome Measures:
Title
Analysis of ATAC-sequence data
Description
An internal pipeline will be used to perform quality control and data pre-processing. Burrows-Wheeler Aligner will be used for read mapping against the hg19 map using default parameters.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective Dose Escalation Cohort Only: Participants must have evaluable disease or measurable disease per RECIST 1.1 criteria Dose Expansion Cohort Only: Participants must have a diagnosis of NUT carcinoma (NC) based on standard criteria for the disease, with diagnostic testing performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory: Ectopic expression of NUT protein (> 50% tumor nuclei) as determined by immunohistochemistry (IHC) testing, OR Detection of the NUT gene translocation as determined by fluorescence in situ hybridization (FISH) testing Participants must have measurable disease per RECIST 1.1 criteria Any number of prior lines of therapy in the metastatic setting are allowed, including prior BET inhibitor therapy and prior CDK4/6 inhibitor therapy Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy Participants may have previously undergone surgical resection Age >= 12 years. Patients 12-17 years of age must be > 40 kg at enrollment. Patients 12-17 years of age will not participate in the mandatory tumor biopsies. Since there is no data on patients less than 18 years of age, this population may require lower doses and additional safety precautions and should be closely monitored Eastern Cooperative Oncology Group (ECOG) performance status =< 2 for participants >= 16 years of age, Lansky >= 50% if < 16 years of age Hemoglobin >= 8 g/dL; Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion Absolute neutrophil count >= 1.5 x 10^9/L Platelets >= 1 x 10^11/L Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) for age. Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN for age Serum or plasma creatinine =< 1.5 x institutional ULN OR calculated creatinine clearance >= 50 mL/min (via the chronic kidney disease epidemiology (CKD-EPI) glomerular filtration rate estimation for participants >= 18 years old, or Schwartz formula for participants 12 - 17 years old) 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 and has been clinically stable for at least 1 month. Patients must meet the following criteria: Disease outside the CNS is present Recovery from acute toxicity associated with the treatment to =< CTCAE grade 1 or baseline (with the exception of alopecia), with no requirement for escalating doses of corticosteroids over the past 7 days 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 should be New York Heart Association Functional Classification of class 2B or better Ability to swallow and retain oral medications The effects of ZEN00364 and abemaciclib on the developing human fetus are unknown. For this reason and because BETi and CDKi-inhibiting agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women of child-bearing potential must have a negative pregnancy test prior to study entry. 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. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 weeks after completion of ZEN003694 and abemaciclib administration For female subjects of child-bearing potentially receiving ZEN003694, hormonal means of birth control alone, such as oral, injectable, dermal, subdermal or topical contraceptives are NOT acceptable forms of birth control given that their efficacy has not been evaluated when given in combination with the investigational drugs. "Adequate contraception" is defined as the following: Contraceptive methods with a failure rate of =< 1% used in combination with the barrier method. The following contraceptive methods are acceptable to use in combination with the barrier method: intrauterine device (IUD), intrauterine system (IUS), or oral contraceptive pills (OCPs) that meet the < 1% failure rate as stated in the product label. Note: Hormonal IUDs/OCPs may only be used if the following criteria are met: male condoms are required AND subjects are informed of the potential for reduced systemic hormone levels from the IUD/OCP when taking ZEN003694. Alternatively, male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records Male subjects with female partners of child-bearing potential must use one of the following contraceptive methods: Vasectomy with documentation of azoospermia OR Condom use PLUS partner use of a highly effective contraceptive (=< 1% rate of failure per year) such as intrauterine device or system, or hormonal birth control such as contraceptive subdermal implant, combined estrogen and progestogen oral contraceptive, injectable progestogen, contraceptive vaginal ring, or percutaneous contraceptive patches Male subjects should not donate sperm while on study and for 12 weeks after the last dose of study medication. Male subjects whose partners are or become pregnant must continue to use condoms for 12 weeks after the last dose of study medication Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available may be eligible after discussion with the Principal Investigator of this study. There will be a separate assent process for minors Exclusion Criteria: Participants who have had cytotoxic chemotherapy, immunotherapy, or other investigational therapy within 2 weeks prior to entering the study. There is a two week required washout period for previous BET inhibitor therapy Participants who have had radiotherapy within at least 2 weeks prior to entering the study. Stereotactic radiosurgery (SRS) within 1 week prior to entering the study will be allowed Participants who have had major surgery within 3 weeks prior to entering the study Participants who have received tyrosine kinase inhibitors (TKIs) or small molecules within 5 half-lives or 1 week (whichever is shorter) of study entry Patients who are receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or abemaciclib Patients requiring medications or substances that are strong inhibitors or strong inducers of CYP3A4 or CYP3A enzymes are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 and abemaciclib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 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 Patients with uncontrolled intercurrent illness, including but not limited to: ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance < 30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea that, in the judgment of the investigator, would preclude participation in this study Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. As proton pump inhibitors (PPIs), H2 receptor antagonists, and antacids may alter the pharmacokinetics of ZEN003694 by reducing ZEN003694 exposure, patients receiving proton pump inhibitors are ineligible. If H2 blockers or other acid reducing agents are used concomitantly with ZEN003694, a staggered dosing schedule should be used. 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 Pregnant women are excluded from this study because ZEN003694 is a BETi 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 ZEN003694, breastfeeding should be discontinued if the mother is treated with ZEN003694. These potential risks may also apply to other agents used in this study Fridericia's correction formula (QTcF) >= 450 msec on screening electrocardiogram (ECG) (machine or manual read allowed). Patients should avoid medications which prolong the QT Patients receiving any medications or substances that are Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) or Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed Patients with radiation to > 25% of the bone marrow Patients who have had a bone-targeted radionuclide within 6 weeks of the first dose of ZEN003694 Myocardial infarction or unstable angina within 6 months prior to the first dose of ZEN003694 Impairment of gastrointestinal function that may significantly alter the absorption of ZEN003694 and/or abemaciclib The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jia Luo
Organizational Affiliation
Dana-Farber - Harvard Cancer Center LAO
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
877-442-3324
First Name & Middle Initial & Last Name & Degree
Jia Luo
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
877-632-6789
Email
askmdanderson@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Sarina A. Piha-Paul

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing URL
https://grants.nih.gov/policy/sharing.htm

Learn more about this trial

Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma and Other Solid Tumors

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