NUT Midline Carcinoma Non-Small Cell Lung Cancer Triple-Negative Breast Cancer Castration-Resistant Prostate Cancer MedDRA version: 18.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.1 Level: LLT Classification code 10076506 Term: Castration-resistant prostate cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts
Conditions
Interventions
Product Name: MK-8628 (formerly known as OTX015)
Product Code: MK-8628 (formerly known as OTX015)
Pharmaceutical Form: Capsule
INN or Proposed INN: OTX015
CAS Number: 204587-26-8
Concentration unit: m
Sponsors
Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: In order to be eligible for participation in this trial, the subject must: 1.Have signed informed consent/assent prior to initiation of any study-specific procedures and treatment. For study subjects who are legal minors, the parent or legal guardian must also sign the consent/assent form. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical research. 2.Have 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 subject: a)NUT midline carcinoma (NMC)(ectopic expression of NUT protein as determined by IHC and/or detection of BRD-NUT gene translocation as determined by FISH) b)Non-small cell lung cancer (NSCLC): all comers without gene rearrangement or mutational restrictions c)Triple negative breast cancer (TNBC) defined according to ASCO recommendations d)Castration-resistant prostate cancer (CRPC) 3.Have at least one measurable lesion as per RECIST version 1.1., except for CRPC subjects who may be enrolled with objective evidence of disease as per Prostate Cancer Clinical Trials Working Group (PCWG2) criteria. 4.For NSCLC, TNBC and CRPC subjects, be age > or = 18 years at the time of informed consent; for NMC subjects, be age > or = 16 years at the time of informed consent. 5.Have a life expectancy > or = 3 months. 6.Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ? 1. 7.Demonstrate adequate organ function (adequate bone marrow reserve, renal and liver function) 8.Have an interval of > or = 3 weeks since chemotherapy (> or = 6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy (including investigational) or surgical intervention resection, or > or = 3 half-lives for monoclonal antibodies, or > or = 5 half-lives for other non-cytotoxic agents (whichever is longer). 9.CRPC subjects 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.Subjects receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before initiating study treatment 11.Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 12.Female subjects of childbearing potential should be willing to use an adequate method of contraception as outlined in section 5.7.3? Contraception, for the course of the study through 60 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 13.Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.7.3 ? Contraception, starting with the first dose of trial treatment through 60 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Are the trial subjects under 18? yes Number of subjects for this age range: 5 F.1.2 Adults (18-64 years) yes F.1.2.1 Nu
Exclusion criteria
Exclusion criteria: The subject must be excluded from participating in the trial if the subject: 1.Has inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of MK-8628. 2.Has persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ? grade 2 National Cancer Institute (NCI)-CTCAE v. 4.0 is accepted. 3.Has known primary CNS malignancy or symptomatic or untreated CNS metastases. 4.Has a history of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of signing informed consent. 5.Has other serious illness or medical condition, such as active infection, unresolved bowel obstruction, psychiatric disorders, or cerebrovascular accident (within 1 year of study entry). 6.Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 7.Has known active Hepatitis B (e.g. hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (e.g. hepatitis C viral [HCV] RNA [qualitative] is detected). 8.Has any of the following cardiac-related conditions: a.Congestive heart failure or angina pectoris (except if medically controlled) b.Previous history of myocardial infarction (within 1 year of study entry) c.Uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg, and/or diastolic blood pressure > 90 mmHg, and not adequately managed by anti-hypertensive medication) d.Uncontrolled arrhythmias 9.Has participated in another clinical trial or treatment with any investigational drug (excluding anticancer treatments) within 30 days prior to study entry. 10.Has other concomitant anticancer treatment, except the use of anti-androgens in CRPC subjects. 11.Has concomitant therapy with strong CYP3A4 inhibitors or inducers. 12.Is currently using 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. 13.Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject?s participation for the full duration of the trial. 14.Is pregnant or breast-feeding.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the recommended phase II dose for single-agent MK-8628 administered orally to subjects with selected solid tumors.;Secondary Objective: For single-agent MK-8628 administered orally to subjects with selected solid tumors: (1)To assess the safety and tolerability; (2)To characterize pharmacokinetic and pharmacodynamic parameters; (3)To evaluate antitumor activity using objective response rate, duration of response and disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2) as assessed by investigator radiologic review.;Primary end point(s): The primary objective of this trial is to determine the recommended phase II dose (RP2D) of MK-8628. Selecting the RP2D will involve a multi-faceted decision taking into account safety, tolerability, early efficacy signal, PK exposure and PD markers. The primary endpoint driving dose selection is the DLT rate, with weight given to the highest DL tolerated (<25% DLT rate). All other facets will be considered supportive. It is important to note that dose selection in this study aims to assess a RP2D range, with other factors aside from those mentioned above, such as target engagement, contributing to refining the dose selection for phase 2. This will be further evaluated in subsequent clinical investigations in either monotherapy or combination trials.;Timepoint(s) of evaluation of this end point: DLTs are monitored continuously during the first cycle of treatment (21 days) for each dose level. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.Secondary Safety Endpoints A secondary objective of this trial is to determine the safety and tolerability of MK-8628 across subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC) included in this trial. Safety will be assessed in subjects who have received MK-8628 by determining the RP2D and quantifying and grading reported Adverse Events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Attribution to drug, time-of-onset, duration of the event, resolution, and any concomitant medications administered will be recorded. AEs to be analyzed include but are not limited to all AEs, events of clinical interest (ECI), serious adverse events (SAE), fatal SAEs, and laboratory changes. Pharmacokinetic Endpoints Plasma parameters of MK-8628 as appropriate and according to analyses performed (non-compartmental or nonlinear mixed effect modelling) will be determined and may include trough (Cmin) and peak (Cmax) concentrations, time to peak concentration (Tmax), AUC[0-?], volume of distribution at steady state (Vdss), terminal half-life (t1/2), steady state, and total clearance (CL). PK data for MK-8628 will be interpreted in terms of safety findings and compared with historical data. Incidence and severity of AEs along with PK parameters will be analyzed in relation to the most pertinent biomarker(s), if any. Pharmacodynamic Endpoints Inhibition of BET proteins by MK-8628 leads to alterations in the transcription of messenger RNA (mRNA) at loci most sensitive to disruption of BET activity. These are considered target genes. Changes in expression, measured via mRNA, of prespecified target genes* will be used as PD biomarkers to assess target engagement of BET proteins by MK-8628. (*Note: the following non-exhaustive list of target genes may be considered for testing: Bcl2, IL7R, and MYC as down-regulated target genes; CSRNP2, HEXIM1, and HIST1H2BK as up-regulated target genes.) A range of PD biomarkers w | — |
Countries
Belgium, Canada, France, Spain, Switzerland, United States
Contacts
Public ContactInvestigación Clínica
Merck Sharp & Dohme de España S.A.
Outcome results
None listed