| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Solid Tumors - first-line, advanced/metastatic NSCLC and second-line (and beyond) advanced/metastatic SCLC and Melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with advance solid tumor such as those found in the lungs and skin |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059514 |
| E.1.2 | Term | Small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025671 |
| E.1.2 | Term | Malignant melanoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To determine the safety and tolerability of MK-1308 in combination with pembrolizumab and to establish a preliminary recommended Phase 2 dose (RPTD) when used in combination with pembrolizumab (Dose Escalation and Confirmation phases)
2. To determine the safety and tolerability of MK-1308 as monotherapy in the efficacy expansion phase (Efficacy Expansion phase)
3. To determine the safety and tolerability of MK-1308A (Coformulation phase)
4. To evaluate ORR as assessed by BICR per RECIST 1.1 in the efficacy expansion phase |
|
| E.2.2 | Secondary objectives of the trial |
1. To characterize the PK profiles and incidence of ADA, as appropriate, of pembrolizumab, of MK-1308 as monotherapy, and of MK-1308 when used in combination and in coformulation with pembrolizumab in the dose escalation, dose confirmation, efficacy expansion, and coformulation phases.
2. To characterize PK profiles and incidence of ADA of both MK-1308 and pembrolizumab in Chinese participants when the study drugs are administered as a coformulated product (MK-1308A).
3. To evaluate ORR as assessed by investigator per RECIST 1.1 in the dose escalation, dose confirmation, and coformulation phases.
4. To evaluate DOR per RECIST 1.1 as assessed by BICR in the efficacy expansion phases |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male and female participants who are at least 18 years of age on the day of signing consent will be enrolled.
1) For Dose Escalation Phase: Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor (except NSCLC for Cohorts 2 and 3) by pathology report and have received, been intolerant to, been ineligible for or refused all treatment known to confer clinical benefit.
2) For Dose Confirmation Phase, Arms A, B, C, E: Have newly diagnosed histologically or cytologically-confirmed stage IIIB/stage IV NSCLC:
The participant must not have received prior systemic treatment for advanced NSCLC or must have received previous neoadjuvant and adjuvant chemotherapies ≥6 months before dosing of study drug if prior systemic treatment was given for early stage disease. Diagnosis must be stated in a pathology report and pathologically confirmed at the study site by the investigator.
3) For Dose Confirmation Phase, Arm D: Have histologically- or cytologically confirmed metastatic (Stage III/IV) SCLC with progressive disease after at least one platinum-based chemotherapy regimen. Participants with platinum-sensitive (relapse ≥90 days after chemotherapy) or platinum-resistant (relapse <90 days after or during chemotherapy) disease are eligible. Diagnosis must be stated in a pathology report and pathologically confirmed at study site by the investigator.
4) Have measurable disease by RECIST 1.1 as assessed by the local site investigator/radiology. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
5) Have a performance status of 0 or 1 on ECOG Performance Scale.
6) Demonstrate adequate organ function. All screening labs should be performed within the screening period.
7) female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
Is not a WOCBP OR
Is a WOCBP and using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 120 days after the last dose of pembrolizumab or MK-1308A, whichever comes last. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine and within 72 hours for serum before the first dose of study intervention.
8) Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication.
9) Male participants with a female partner(s) of child-bearing potential must agree to use an adequate method of contraception during the treatment period plus an additional 120 days after the last dose of study treatment and refrain from donating sperm during this period.
10) Has voluntarily agreed to participate by giving documented informed consent for the trial. The participant may also provide consent/assent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.
11) Must submit an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. If submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut.
12) For Efficacy Expansion Phase Arms F and G:
a) Have histologically/cytologically-confirmed unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8, not amenable to local therapy.
b) Have at least 1 measurable lesion by CT or MRI per RECIST 1.1 by BCIR. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol but may be considered as non-target lesions.
c) Participants with unresectable Stage III or Stage IV disease must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies (combinations with anti-CTLA-4 agents will not be allowed).
d) Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1 are eligible. For these participants, the following applies: 1) a second assessment to confirm disease progression beyond recurrence is not required (eg, iRECIST is not required); 2) they must have received at least 2 prior doses of anti-PD-1/ PD-L1 mAb. |
|
| E.4 | Principal exclusion criteria |
1)Has received previous treatment with another agent targeting CTLA4.
2) For Dose Confirmation Phase: Has received previous treatment with another agent targeting PD-1, PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, OX-40, CD137). 3) Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the 1st dose of study therapy, or has not recovered to CTCAE Grade 1 or better from any adverse events that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immunerelated ΑΕs). 4) Has received lung radiation therapy of >30 Gy within 6 months before the first dose of study treatment. 5) Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-1308. 6) Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years. 7) For Cohorts 1-3 and Arms A through E: Has known untreated central nervous system (ie, brain and/or spinal cord) metastases. Has known carcinomatous meningitis. 8) Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE. 9) Previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of pembrolizumab. 10) Has any active infection requiring therapy. 11) Has a history of interstitial lung disease. 12) Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 13) Has a history of inflammatory bowel disease. 14) Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or Ιmmunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment and is allowed. Use of non-systemic steroids is permitted. 15) Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted. 16) Has received a live or live attenuated virus vaccine within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. 17) Participants with known history of HIV (HIV 1/2 antibodies) and/or active Hepatitis B or C, and/or positive HBsAg and HBVDNA. Active Hepatitis C is defined by a positive Hep C Ab result and quantitative HCV RNA results greater than the lower limits of detection of the assay. 18) Has history or current evidence of any condition, therapy, or laboratory abnorm. that might confound the results of the study, interfere with participant’s particip. for the full duration of the study, make administration of the study drugs hazardous or make it difficult to monitor adverse effects such that it is not in the best interest of the participant to participate, in the opinion of the treating Investigator. 19) Has known psychiatric or substance abuse disorders that would interfere with the participant’s ability to cooperate with the requirements of the trial. 20) Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with screening and for up to 120 days following cessation of pembrolizumab or MK‑1308A. 21) Has not fully recovered from any effects of major surgery without significant detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 h before first study drug administration and participants should be recovered. 22) Is taking chronic systemic steroids in doses >10 mg daily of prednisone or equivalent within 7 d prior to first dose of trial treatment. 23) Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. 24) For Arm F and G and and K ONLY:
a) Has known active CNS metastases and/or carcinomatous meningitis. b) Has not had resolution of anti-PD-1 antibody-related AEs. c) Has ocular melanoma (NA for arm K) d) Has mucosal Melanoma(NA for arm K) 25) Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of participants with ≥ Dose Limiting Toxicity (DLT)
2. Number of participants with ≥1 adverse event (AE)
3. Number of participants discontinuing study treatment due to an AE
4. Efficacy Expansion: Number of participants with ≥1 AE
5. Efficacy Expansion: Number of participants discontinuing study treatment due to an AE
6. Coformulation Phase: Number of participants with ≥1 DLT
7. Coformulation Phase: Number of participants with ≥1 AE
8. Coformulation Phase: Number of participants discontinuing study treatment due to an AE
9. Efficacy Expansion: Objective Response Rate (ORR) as assessed by blinded independent central review (BICR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 6 weeks
2. Up to approximately 2.5 years
3. Up to approximately 2 years
4. Up to approximately 2.5 year
5. Up to approximately 2 years
6. Up to 6 weeks
7. Up to approximately 2.5 years
8. Up to approximately 2 years
9. Up to approximately 4 years |
|
| E.5.2 | Secondary end point(s) |
1.Area under the plasma concentration time curve (AUC) of pembrolizumab
2.Maximum concentration (Cmax) of pembrolizumab
3.Minimum concentration (Cmin) of pembrolizumab
4.Number of participants with pembrolizumab anti-drug antibodies (ADAs)
5.AUC of MK-1308
6.Cmax of MK-1308
7.Cmin of MK-1308
8.Number of participants with MK-1308 ADAs
9.Chinese Cohort: AUC of pembrolizumab
10.Chinese Cohort: Cmax of pembrolizumab
11.Chinese Cohort: Cmin of pembrolizumab
12.Chinese Cohort: Number of participants with pembrolizumab ADAs
13.Chinese Cohort: AUC of MK-1308
14.Chinese Cohort: Cmax of MK-1308
15.Chinese Cohort: Cmin of MK-1308
16.Chinese Cohort: Number of participants with MK-1308 ADAs
17.Dose esclation, Dose confirmation, Coformulation: ORR as assessed by investigator based on modified RECIST v1.1
18.Efficacy Expansion: Duration of Response (DOR) as assessed by BICR on modifies RECIST v1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.At designated timepoints (up to ~6 months)
2.At designated timepoints (up to ~6 months)
3.At designated timepoints (up to ~6 months)
4.At designated timepoints (up to ~2 years)
5.At designated timepoints (up to ~6 months)
6.At designated timepoints (up to ~6 months)
7.At designated timepoints (up to ~6 months)
8.At designated timepoints (up to ~2 years)
9.At designated timepoints (up to ~6 months)
10.At designated timepoints (up to ~6 months)
11.At designated timepoints (up to ~2 years)
12.At designated timepoints (up to ~2 years)
13.At designated timepoints (up to ~6 months)
14.At designated timepoints (up to ~6 months)
15.At designated timepoints (up to ~2 years)
16.At designated timepoints (up to ~2 years)
17.Up to ~4 years
18.Up to ~4 years
|
|
| 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 | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 9 |
| 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 | 16 |
| 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 |
| Australia |
| Canada |
| Chile |
| France |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| New Zealand |
| Poland |
| South Africa |
| Spain |
| Sweden |
| United States |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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