AzTrials
AzTrials

NUT Midline CarcinomaPhase 1NCT02259114

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

A Phase 1 study testing Birabresib in people with NUT Midline Carcinoma and Triple Negative Breast Cancer, run by Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Open-label, phase I, non-randomized, multicentric study of single-agent birabresib (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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Birabresib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
47 participants
Where
No sites listed yet
Study dates
23 Oct 2014to 3 Mar 2017
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed informed consent obtained prior to initiation of any study-specific procedures and treatment;
  • 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);
Show all 22Show fewer
  • Pancreatic ductal adenocarcinoma;
  • 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;
  • Age ≥18 years at the time of informed consent;
  • Life expectancy ≥3 months;
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1;
  • 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;
  • 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);
  • 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);
  • Participants receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before initiating study treatment.

Who cannot join

  • Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of birabresib;
  • 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.
  • Known primary central nervous system (CNS) malignancy or CNS involvement;
  • 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;
  • Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or psychiatric disorders;
  • Known human immunodeficiency virus (HIV) positivity;
Show all 11Show fewer
  • Participation in another clinical trial or treatment with any investigational drug within 30 days prior to study entry;
  • Other concomitant anticancer treatment;
  • Concomitant therapy with strong CYP3A4 interfering drugs;
  • Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of birabresib. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted;
  • Pregnant or breast-feeding participants, and men and women with childbearing potential not using effective contraception while on study drug.

About this study

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

Open-label, phase I, non-randomized, multicentric study of single-agent birabresib (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.

Read more

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 birabresib 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 birabresib 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 birabresib 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.

Being tested
Birabresib
Medical subject headings
Triple Negative Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BirabresibDrug

    Also called OTX105, MK-8628

    Birabresib 10, 20 and/or 40 mg oral capsules

Study groups in NCT02259114
Study groupRoleWhat they receive
Continuous Dosing RegimenExperimentalParticipants receive birabresib 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.
Receives: Drug: Birabresib
Days 1-7 Dosing RegimenExperimentalParticipants receive birabresib 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.
Receives: Drug: Birabresib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1

    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.

    Measured: Up to Cycle 1 Day 21 (Up to 21 days)

Secondary outcomes (9)

  1. Number of Participants Who Experienced at Least One Adverse Event (AE)

    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.

    Measured: Up to approximately 17.5 months (Up to 30 days after last dose of study treatment)

  2. Number of Participants Who Discontinued Study Treatment Due to an AE

    The number of participants who discontinued study treatment due to an AE is presented.

    Measured: Up to approximately 16.5 months

  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

    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.

    Measured: Up to approximately 16.5 months

  4. Observed Maximum Plasma Concentration (Cmax) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

  5. Time to Cmax (Tmax) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

  6. Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

  7. Volume of Distribution at Steady State (Vdss) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

  8. Terminal Half-Life (t1/2) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

  9. Total Plasma Clearance (CL) of MK-8628

    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.

    Measured: Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Oct 2014 (estimated)
  2. Study start23 Oct 2014
  3. Primary completion3 Mar 2017
  4. Study completion3 Mar 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
47 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02259114
Sponsor's protocol ID
8628-003
Other IDs
OTX015_108, 2014-002680-15, MK-8628-003, 2014
Status last verified
Jan 2021
First submitted
3 Oct 2014
Last updated
26 Jan 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Publications

  • Lewin J, Soria JC, Stathis A, Delord JP, Peters S, Awada A, Aftimos PG, Bekradda M, Rezai K, Zeng Z, Hussain A, Perez S, Siu LL, Massard C. Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors. J Clin Oncol. 2018 Oct 20;36(30):3007-3014. doi: 10.1200/JCO.2018.78.2292. Epub 2018 May 7.

    PubMed 29733771

  • Vazquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L, Bekradda M, Cvitkovic E, Bertoni F, Frapolli R, D'Incalci M. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017 Jan 31;8(5):7598-7613. doi: 10.18632/oncotarget.13814.

    PubMed 27935867

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Birabresib in people with NUT Midline Carcinoma and Triple Negative Breast Cancer, run by Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02259114, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2021.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in