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.

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.

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 birabresib;
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 birabresib. 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.

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf