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A Dose-Finding Study of MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Adults With Selected Advanced Solid Tumors (MK-8628-003)

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ClinicalTrials.gov Identifier: NCT02259114
Recruitment Status : Completed
First Posted : October 8, 2014
Results First Posted : October 1, 2018
Last Update Posted : October 1, 2018
Sponsor:
Information provided by (Responsible Party):
Oncoethix GmbH

Brief Summary:

Open-label, phase I, non-randomized, multicentric study of single-agent MK-8628 (formerly known as OTX015) administered according to two distinct regimens to participants with selected advanced tumors.

The study will be performed in two parts.

Dose Escalation Part:

This step is designed to determine the maximum tolerated dose (MTD) in each of the two regimens, which will be evaluated in parallel. Participants will receive oral MK-8628 according to:

Continuous Dosing Regimen: continuous, once daily for 21 consecutive days (21-day cycles).

OR Days 1-7 Dosing Regimen: once daily on Days 1 to 7, repeated every 3 weeks (21-day cycles; 1 week ON/2 weeks OFF).

Participants will be sequentially assigned to Continuous Dosing Regimen or Days 1-7 Dosing Regimen according to the next available place and receive MK-8628 at escalating doses levels (DL). Cohorts of 3 participants will be treated, and an additional 3 participants will be treated at the first indication of dose-limiting toxicity (DLT). MTD assessment will be based on the tolerability observed during the first 21 days of treatment.

Expansion Part:

The efficacy of MK-8628 in each of the five indications (i.e., Bromodomain-Nuclear Protein in Testis [BRD-NUT] midline carcinoma, triple negative breast cancer [TNBC], non-small cell lung cancer [NSCLC] harboring a rearrangement Anaplastic Lymphoma Kinase [ALK] gene/fusion protein or Kirsten Ras [KRAS] mutation, castrate-resistant prostate cancer, and pancreatic ductal carcinoma) will be assessed in terms of response (Response Evaluation Criteria in Solid Tumors v1.1 [RECIST v1.1] or Prostate Cancer Clinical Trials Working Group 2 [PCWG2]) using a selected regimen.


Condition or disease Intervention/treatment Phase
NUT Midline Carcinoma Triple Negative Breast Cancer Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation Castrate-resistant Prostate Cancer CRPC Pancreatic Ductal Adenocarcinoma Drug: MK-8628 Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 47 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB Trial With OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Patients With Selected Advanced Solid Tumors
Actual Study Start Date : October 23, 2014
Actual Primary Completion Date : March 3, 2017
Actual Study Completion Date : March 3, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Continuous Dosing Regimen
Participants receive MK-8628 capsules once daily in a fasted state in the morning on Days 1-21 of each 21-day cycle. Starting dose for dose escalation is 80 mg.
Drug: MK-8628
MK-8628 10, 20 and/or 40 mg oral capsules
Other Name: OTX105

Experimental: Days 1-7 Dosing Regimen
Participants receive MK-8628 capsules once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. Starting dose for dose escalation is 100 mg.
Drug: MK-8628
MK-8628 10, 20 and/or 40 mg oral capsules
Other Name: OTX105




Primary Outcome Measures :
  1. Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 [ Time Frame: Up to Cycle 1 Day 21 (Up to 21 days) ]
    A DLT was defined as any of the following toxicities that were considered by the investigator to be related to MK-8628: Hematologic toxicity: Grade 4 hematologic toxicity or febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with bleeding or lasting >7 days; Non-hematologic toxicity: Grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed with supportive care, Grade 3 or 4 laboratory abnormality, with or without symptoms, lasting >48 hours, Intolerable Grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay >7 days with or without dose reduction, Designated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver test abnormalities; Treatment delay >2 weeks or dose reduction requirement for initiating Cycle 2.


Secondary Outcome Measures :
  1. Number of Participants Who Experienced at Least One Adverse Event (AE) [ Time Frame: Up to approximately 17.5 months (Up to 30 days after last dose of study treatment) ]
    An AE is defined as any untoward medical occurrence associated with use of study treatment in humans, whether or not considered treatment related. The number of participants who experienced at least one AE is presented.

  2. Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 16.5 months ]
    The number of participants who discontinued study treatment due to an AE is presented.

  3. Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria [ Time Frame: Up to approximately 16.5 months ]
    The best overall response was the best response recorded from the start of the study treatment until the end of treatment. RECIST 1.1 response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

  4. Observed Maximum Plasma Concentration (Cmax) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for pharmacokinetic (PK) analysis of the observed Cmax of MK-8628. The observed Cmax of MK-8628 after administration is presented.

  5. Time to Cmax (Tmax) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for PK analysis of the Tmax of MK-8628. The Tmax of MK-8628 after administration is presented.

  6. Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for PK analysis of the AUC0-∞ of MK-8628. The AUC0-first is AUC0-∞ which is derived from the post-hoc estimate of CL/F from the population model. The AUC0-∞ of MK-8628 after administration is presented.

  7. Volume of Distribution at Steady State (Vdss) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for PK analysis of the Vdss of MK-8628. The Vdss of MK-8628 after administration is presented.

  8. Terminal Half-Life (t1/2) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for PK analysis of the t1/2 of MK-8628. The t1/2 of MK-8628 after administration is presented.

  9. Total Plasma Clearance (CL) of MK-8628 [ Time Frame: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose ]
    Blood samples were obtained at specified time points for PK analysis of the CL of MK-8628. The CL of MK-8628 after administration is presented.



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:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment;
  2. Histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the patient:

    • NUT midline carcinoma (ectopic expression of NUT protein as determined by immunohistochemistry (IHC) and/or detection of BRD-NUT gene translocation as determined by fluorescence In situ hybridization [FISH]);
    • Triple negative breast cancer defined according to American Society of Clinical Oncology (ASCO) recommendations (Hammond et al., 2010; Wolff et al., 2007);
    • Non-small cell lung cancer harboring a rearranged ALK gene/fusion protein (FISH or IHC) or KRAS mutation (as defined by any molecular analysis);
    • Castrate-resistant prostate cancer (CRPC);
    • Pancreatic ductal adenocarcinoma;
  3. At least one measurable lesion as per RECIST version 1.1., except for CRPC participants who may be enrolled with objective evidence of disease as per PCWG2 criteria;
  4. Age ≥18 years at the time of informed consent;
  5. Life expectancy ≥3 months;
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1;
  7. Adequate bone marrow reserve, renal and liver function:

    • Absolute neutrophil count ≥1.5 x10^9/L,
    • Platelet count ≥150 x10^9/L,
    • Hemoglobin ≥9 g/dL,
    • Creatinine clearance ≥30 mL/min calculated according to the Cockroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for participants aged >65 years,
    • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.25 x ULN (in case of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed),
    • Serum albumin ≥2.8 g/dL,
    • International Normalized Ratio (INR) ≤1.5 x ULN or INR <3 for participants treated with antivitamin K;
  8. An interval of ≥3 weeks since chemotherapy (≥6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or ≥3 half-lives for monoclonal antibodies, or ≥5 half-lives for other non-cytotoxic agents (whichever is longer);
  9. CRPC participants must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is <50 ng/dL (<1.7 nmol/L);
  10. Participants receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before initiating study treatment.

Exclusion Criteria:

  1. Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of MK-8628;
  2. Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 is accepted.
  3. Known primary central nervous system (CNS) malignancy or CNS involvement;
  4. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of study entry;
  5. Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or psychiatric disorders;
  6. Known human immunodeficiency virus (HIV) positivity;
  7. Participation in another clinical trial or treatment with any investigational drug within 30 days prior to study entry;
  8. Other concomitant anticancer treatment;
  9. Concomitant therapy with strong CYP3A4 interfering drugs;
  10. Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of MK-8628. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted;
  11. Pregnant or breast-feeding participants, and men and women with childbearing potential not using effective contraception while on study drug.

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): NCT02259114


Sponsors and Collaborators
Oncoethix GmbH
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by Oncoethix GmbH:
Study Protocol  [PDF] November 19, 2015
Statistical Analysis Plan  [PDF] February 9, 2017


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Oncoethix GmbH
ClinicalTrials.gov Identifier: NCT02259114     History of Changes
Other Study ID Numbers: 8628-003
OTX015_108 ( Other Identifier: OncoEthix )
2014-002680-15 ( EudraCT Number )
MK-8628-003 ( Other Identifier: Merck Protocol Number )
First Posted: October 8, 2014    Key Record Dates
Results First Posted: October 1, 2018
Last Update Posted: October 1, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Triple Negative Breast Neoplasms
Prostatic Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Breast Neoplasms
Breast Diseases
Skin Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Prostatic Diseases