| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
NUT Midline Carcinoma
Non-Small Cell Lung Cancer
Triple-Negative Breast Cancer
Castration-Resistant Prostate Cancer
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the recommended phase II dose for single-agent MK-8628 administered orally to subjects with selected solid tumors. |
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≥ 18 years at the time of informed consent; for NMC subjects, be age ≥ 16 years at the time of informed consent.
5.Have a life expectancy ≥ 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 ≥ 3 weeks since chemotherapy (≥ 6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy (including investigational) 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 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.
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| E.4 | Principal 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. |
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| E.5 End points |
| E.5.1 | 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DLTs are monitored continuously during the first cycle of treatment (21 days) for each dose level. |
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| E.5.2 | 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 will be explored in surrogate samples from all subjects treated, using appropriate assays to establish target engagement. Rather than rely on gene expression changes in cancer cells, these PD biomarkers will be based on current PD knowledge from translational studies of mouse and human whole blood. Using RNA extracted from whole blood samples collected both prior to and following administration of MK-8628, messenger RNA transcript profiling may be performed to assess gene expression and evaluate whether changes in specific genes or sets of genes may represent a PD biomarker of response. Potential limitations of this assay include patient-to-patient variability and a small effect size of induction or repression upon treatment with MK-8628. Due to these limitations, the PD endpoint is considered to be qualitative given the assay may not be able to differentiate target engagement between the MK-8628 doses examined in this study.
Secondary Efficacy Endpoints: RECIST or PCWG -based Response Rate
A secondary efficacy objective of this trial is to evaluate the anti-tumor activity of MK-8628 in subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC). Secondary efficacy endpoints include (1) Objective Response Rate (ORR), defined as the percentage of subjects who have achieved confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2), as assessed by investigator radiologic review; (2) Duration of Response (DOR), defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first; and (3) Disease Control Rate (DCR), defined as the percentage of subjects who have achieved stable disease or confirmed CR or confirmed PR according to RECIST v1.1 or PCWG2, by the investigator review.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Safety Endpoints: AEs are monitored continuously.
PK Endpoints: Cycle 1 - Day 1; immediately prior to the first dose T0 and 20 min±5min, 1h±10min, 2h15min±10min, 3h15min±10min, 8h±1h, and 12h±2h, Day 8 ±1 days, Day 15 ±2 days, and Day 22 ±3 days.
Pharmacodynamic Endpoints: Cycle 1 - Day 1: immediately prior to the first dose T0 and 3h15min±10min, 8h±1h, and 12h±2h and Day 8 ±1 day.
Secondary Efficacy Endpoints: For tumor evaluation, a CT, MRI and/or chest X-ray will be performed on Day 1 ± 3 days of every 2nd cycle A bone scan is mandatory for CRPC subjects and will be performed on Day 1 ± 3 days of every 4th cycle(every 3 months).Prostate Specific Antigen measurements will be performed every 4 cycles on a schedule coinciding with the CRPC subjects’ bone scans.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Spain |
| Switzerland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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