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Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT05111561
Recruitment Status : Suspended (Unacceptable Toxicity)
First Posted : November 8, 2021
Last Update Posted : October 6, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 5, 2021
First Posted Date  ICMJE November 8, 2021
Last Update Posted Date October 6, 2022
Actual Study Start Date  ICMJE March 15, 2022
Estimated Primary Completion Date March 14, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 23, 2021)
  • Incidence of dose limiting toxicities (Part 1 [Dose Escalation]) [ Time Frame: Up to 28 days from treatment start date ]
    Defined as the incidence of clinically significant adverse events or abnormal laboratory values thought to be at least possibly related to the study treatment occurring during the first cycle.
  • Incidence of adverse events (Part 2 [Dose Expansion]) [ Time Frame: Up to 30 days after last treatment dose ]
    Including but not limited to treatment-emergent AEs, severe adverse events (SAEs), deaths, and clinical laboratory abnormalities, as assessed by the NCI CTCAE v5.0.
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2021)
  • Incidence of dose limiting toxicities (Part 1 [Dose Escalation]) [ Time Frame: Up to 28 days ]
  • Incidence of adverse events (Part 2 [Dose Expansion]) [ Time Frame: Up to 30 days after last dose ]
    Including but not limited to treatment-emergent AEs, serve adverse events (SAEs), deaths, and clinical laboratory abnormalities, as assessed by the NCI CTCAE v5.0.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2021)
  • Incidence of adverse events (AEs) (Part 1 [Dose Escalation]) [ Time Frame: Up to 30 days after last treatment dose ]
    Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Toxicity will be summarized by grade and type using descriptive statistics, including frequency and 95% confidence interval.
  • Pharmacokinetic (PK) parameters (Part 1 [Dose Escalation]) [ Time Frame: Days 2, 8, 15, and 16 of cycle 1 ]
    PK parameters will be estimated using non-compartmental method(s) and correlated with PD endpoints using non-parametric statistics.
  • Overall response rate (ORR) [ Time Frame: Up to 2 years from treatment start date ]
    Defined as the percentage of participants who have a partial or complete response to the treatment. Descriptive statistics will be used to summarize ORR.
  • Disease control rate (DCR) [ Time Frame: Up to 4 months from treatment start date ]
    Defined as the percentage of participants that have achieved complete response, partial response or stable disease after treatment. Descriptive statistics will be used to summarize DCR.
  • Duration of response (DOR) [ Time Frame: Up to 2 years from treatment start date ]
    Defined as the length of time from treatment start date during the which the tumor does not grow. Kaplan-Meier method will be used to estimate DOR.
  • Progression free survival (PFS) [ Time Frame: Up to 2 years from treatment start date ]
    Defined as the length of time during and after the study treatment during which the tumor does not grow. Kaplan-Meier method will be used to estimate PFS.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2021)
  • Incidence of adverse events (AEs) (Part 1 [Dose Escalation]) [ Time Frame: Up to 30 days after last dose ]
    Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Toxicity will be summarized by grade and type using descriptive statistics, including frequency and 95% confidence interval.
  • Pharmacokinetic (PK) parameters (Part 1 [Dose Escalation]) [ Time Frame: Days 2, 8, 15, and 16 of cycle 1 ]
    PK parameters will be estimated using non-compartmental method(s) and correlated with PD endpoints using non-parametric statistics.
  • Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    Descriptive statistics will be used to summarize ORR.
  • Disease control rate (DCR) [ Time Frame: Up to 2 years ]
    Descriptive statistics will be used to summarize DCR.
  • Duration of response (DOR) [ Time Frame: Up to 2 years ]
    Kaplan-Meier method will be used to estimate DOR.
  • Progression free survival (PFS) [ Time Frame: Up to 2 years ]
    Kaplan-Meier method will be used to estimate PFS.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer
Official Title  ICMJE A Phase 1 Study of ZEN003694 in Combination With Binimetinib in Solid Tumors With RAS Pathway Alterations and Triple Negative Breast Cancer
Brief Summary This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with Binimetinib in treating patients with solid tumors that carry RAS alterations and that have spread to other places in the body (advanced/metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an oral medication with potential anticancer activity. It is an inhibitor of a family of proteins called bromodomain and extra-terminal (BET) which play important role during development and cellular growth. ZEN003694 may stop the growth of tumor cells that produce BET. Binimetinib is in a class of medications called kinase inhibitors. It works by blocking the action proteins called MEK1 and MEK2, that signal cancer cells to multiply. It may help keep cancer cells from growing and spreading. There is pre-clinical evidence that using ZEN003694 and binimetinib together may shrink or stabilize cancers studied in this trial. There are two parts of this study; dose escalation and dose expansion. In the dose escalation part of this study, different people will get different doses of the study drugs ZEN003694 and binimetinib. In the dose expansion part of this study, the highest dose with manageable side effects will be given to additional people. This will help to understand the side effects that may happen with this drug combination.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 [ZEN-3694]) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with rat sarcoma virus oncogene homolog (RAS) pathway alterations. (Part 1 [Dose Escalation]) II. To evaluate the safety and toxicity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 2 [Dose Expansion])

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of ZEN003694 (ZEN-3694) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with RAS pathway alterations. (Part 1 [Dose Escalation]) II. To characterize the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) when given in combination with binimetinib. (Part 1 [Dose Escalation]) III. To observe and record the preliminary antitumor activity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 1 [Dose Escalation]) IV. To determine the effects of ZEN003694 (ZEN-3694) and binimetinib when given in combination on patient survival and other metrics of clinical activity. (Part 2 [Dose Expansion]) IVa. To evaluate objective response rate (ORR). IVb. To evaluate progression-free survival (PFS). IVc. To evaluate duration of response (DOR). IVd. To evaluate disease control rate (DCR) at 4 months.

EXPLORATORY OBJECTIVES:

I. To characterize the PK of the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 [Dose Expansion]) II. To identify biomarkers of sensitivity and response to the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 [Dose Expansion]) III. To determine histone H3 acetylated at lysine 27 (H3K27ac) levels via chromatin immunoprecipitation sequencing (ChIPseq) on tumor biopsy specimen. (Part 2 [Dose Expansion]) IV. To determine the open chromatin regions in response to the ZEN003694 (ZEN-3694) and binimetinib combination using assay for transposase-accessible chromatin sequencing (ATACseq). (Part 2 [Dose Expansion])

OUTLINE: This is a dose-escalation study of ZEN-3694 with fixed dose binimetinib followed by a dose expansion.

Patients receive ZEN-3694 orally (PO) once daily (QD) and binimetinib 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. During the dose expansion phase, patients will have two mandatory biopsies - one before beginning the study and the second at day 15 of cycle 1. The study biopsy takes small pieces of cancer tissue from patient's body to look for markers (substances made by, on, or in tumor cells) related to how the study treatment works.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Refractory Malignant Solid Neoplasm
  • Triple-Negative Breast Carcinoma
  • Unresectable Malignant Solid Neoplasm
Intervention  ICMJE
  • Drug: BET Bromodomain Inhibitor ZEN-3694
    Given PO
    Other Names:
    • BETi ZEN-3694
    • ZEN 3694
    • ZEN-3694
    • ZEN003694
  • Drug: Binimetinib
    Given PO
    Other Names:
    • ARRY-162
    • ARRY-438162
    • MEK162
    • Mektovi
Study Arms  ICMJE Experimental: Treatment (ZEN-3694, binimetinib)
Patients receive ZEN-3694 orally (PO) once daily (QD) and binimetinib 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. During the dose expansion phase, patients will have two mandatory biopsies - one before beginning the study and the second at day 15 of cycle 1. The study biopsy takes small pieces of cancer tissue from patient's body to look for markers (substances made by, on, or in tumor cells) related to how the study treatment works.
Interventions:
  • Drug: BET Bromodomain Inhibitor ZEN-3694
  • Drug: Binimetinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: November 5, 2021)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 14, 2024
Estimated Primary Completion Date March 14, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed advanced/metastatic or unresectable solid tumor that is refractory to standard therapy or has relapsed after standard therapy
  • Patients must have one of the following:

    • For Part 1 and 2 -

      • Triple negative breast cancer (TNBC) (estrogen receptor =< 1%, progesterone receptor =< 1%, human epidermal growth factor receptor 2 0-1+ or non-amplified)
      • Solid tumor with genomic alteration(s) activating RAS signaling including activating KRAS, NRAS, HRAS, or BRAF mutations, inactivating NF1 mutations, or BRAF fusions

        • Genomic alterations should be identified locally by next generation sequencing (NGS). Patient genomic reports will be reviewed by the MD Anderson Cancer Center (MDACC) Precision Oncology Decision Support team prior to initiation of study treatment
  • For Part 1, patients can have evaluable or measurable disease. For Part 2, patients must have measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
  • Patients must be >= 4 weeks beyond treatment with any chemotherapy (6 weeks for nitrosoureas or mitomycin C) or other investigational therapy to include hormonal, biological, or targeted agents; or at least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter at the time of study treatment initiation. Patients must be >= 4 weeks beyond radiotherapy
  • Age >= 18 years. Because no dosing or adverse events (AE) data are currently available on the use of binimetinib and ZEN003694 (ZEN-3694) in patients < 18 years of age, children are excluded from this study
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 125,000/mcL
  • Hemoglobin >= 8 g/dL or >= 5.6 mmol/L
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) OR < 2.0 x ULN in patients with documented Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  • Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
  • Prothrombin time =< 1.5 x ULN
  • Partial thromboplastin time =< 1.5 x ULN
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this stud
  • 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 by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to the first dose of study treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
  • 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 study
  • 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 study, patients should be class 2B or better
  • Patients must have corrected QT (QTc) < 450 msec
  • The effects of ZEN003694 (ZEN-3694) and binimetinib on the developing human fetus are unknown. For this reason and because BETi agents are known to be teratogenic, women of childbearing potential and men 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 4 months after the completion of ZEN003694 (ZEN-3694) and binimetinib 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ZEN003694 (ZEN-3694) and binimetinib administration
  • 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

Exclusion Criteria:

  • Patients who have not recovered from AEs due to prior anticancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia
  • Patients who are receiving any other investigational agents
  • Breast cancer patients with a prior history of hormone receptor positivity will not be eligible
  • Patients with PI3K pathway activating genomic alterations including inactivating mutations/deletions in PTEN and PIK3R1, amplifications in PIK3CA, and activating mutations in PIK3CA, Akt, or mTOR will not be eligible
  • Prior therapy with BET, RAF, MEK, or ERK inhibitor
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694) and binimetinib
  • Patients requiring therapeutic doses of anticoagulation are excluded. Patients taking low-dose (prophylactic) anticoagulation (e.g., low-molecular weight heparin, low-dose warfarin, fondaparinux) are allowed
  • 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 ZEN003694 (ZEN-3694) and binimetinib are a BETi and MEK inhibitor agent, respectively, with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with ZEN003694 (ZEN-3694) and binimetinib, breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694) and binimetinib
  • Patient has a history of cerebrovascular accident, myocardial infarction, or unstable angina within the previous 6 months prior to study treatment initiation
  • Patients with any medical condition or diagnosis that would likely impair absorption of an orally administered drug (e.g., gastrectomy, ileal bypass, chronic diarrhea, gastroparesis) are excluded
  • Patient has a history of retinal vein occlusion
  • Patient has a history of pneumonitis or interstitial lung disease
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05111561
Other Study ID Numbers  ICMJE NCI-2021-11793
NCI-2021-11793 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10449 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
10449 ( Other Identifier: CTEP )
UM1CA186688 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Current Responsible Party National Cancer Institute (NCI)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sarina A Piha-Paul University of Texas MD Anderson Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date October 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP