MK 3475 With or Without Talimogene Laherparepvec in Unresected Melanoma

• Register: EUCTR
• Last refreshed on: 19 April 2021
• Main ID: EUCTR2014-000185-22-ES
• Date of registration: 06/08/2014
• Prospective Registration: Yes
• Primary sponsor: Amgen Inc.
• Public title: MK 3475 With or Without Talimogene Laherparepvec in Unresected Melanoma
• Scientific title: A Phase 1b/2, Multicenter, Open-label Trial of Talimogene Laherparepvec in Combination With MK-3475 for Treatment of Previously Untreated, Unresected, Stage IIIB to IVM1c Melanoma
• Date of first enrolment: 06/11/2014
• Target sample size: 110
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000185-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Czech Republic, Finland, Germany, Greece, Hungary, Italy, Portugal, Spain, Sweden, Switzerland, United States

Contacts

• Name: IHQ medical Info-Clinical Trials
• Affiliation: Amgen (EUROPE) GmbH

• Name: IHQ medical Info-Clinical Trials
• Affiliation: Amgen (EUROPE) GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
Phase 1b and Part 1 of Phase 2:
Male or female age ? 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to IVM1c for whom surgery in not recommended. Subject must be treatment naïve (ie, must not
have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy for unresected stage IIIB to IVM1c melanoma. Subject who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting). However, if the subject received adjuvant therapy, the subject must have completed therapy at
least 6 months prior to enrollment. Subject must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, renal, and coagulation function.

Part 2 of Phase 2:
Subject randomized to arm 2 (MK-3475 monotherapy arm) of part 1 of the phase 2 study must have evidence of PD at week 12 or subsequent tumor assessment visit through month 20
documented by an independent central review committee and confirmed by the investigator ? 4 weeks later using modified irRC. Subject must have ECOG performance status of 0 or 1, and
adequate hematologic, hepatic, renal, and coagulation function
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 57
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 53

Exclusion criteria:
Phase 1b and Part 1 of Phase 2:
Subject must not have clinically active cerebral metastases. Subject with up to 3 cerebral metastases, and neurological performance status of 0 may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gammaknife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment. Subject must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia), or history of other malignancy within the past 3 years with the exceptions of the prior malignancies. Subject must not have received prior talimogene laherparepvec, tumor vaccine, MK-3475, other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, ipilimumab, other cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibitor, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways, even if given in the adjuvant setting. Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic steroids or immunosuppressive agents (except vitiligo or resolved childhood asthma/atopy), or evidence of clinically significant immunosuppression. Subject must not have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.

Part 2 of Phase 2:
Subject must not have stopped MK-3475 treatment in part 1 of phase 2 due to intolerance or reasons other than confirmed PD per modified irRC at week 12 or subsequent tumor assessment visit through month 20. Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic steroids or immunosuppressive agents (except vitiligo or resolved
childhood asthma/atopy), or evidence of clinically significant immunosuppression. Subject must not have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic
keratitis or encephalitis) and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Previously Untreated, Unresected, Stage IIIB to IVM1c Melanoma
MedDRA version: 17.0 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864

Intervention(s)

Product Name: Talimogene Laherparepvec
Product Code: AMG 678
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Talimogene laherparepvec
Current Sponsor code: AMG 678
Other descriptive name: TALIMOGENE LAHERPAREPVEC
Concentration unit: PFU/ml plaque forming unit(s)/millilitre
Concentration type: equal
Concentration number: 1000000-

Product Name: Talimogene Laherparepvec
Product Code: AMG 678
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Talimogene laherparepvec
Current Sponsor code: AMG 678
Other descriptive name: TALIMOGENE LAHERPAREPVEC
Concentration unit: PFU/ml plaque forming unit(s)/millilitre
Concentration type: equal
Concentration number: 100000000-

Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Pembrolizumab
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive name: MK-3475
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: Dependent on phase of study:
-efficacy of talimogene laherparepvec in combination with MK-3475; as compared to MK-3475 alone; as compared to MK-3475 alone in subjects who are either PD-L1-negative or -positive prior to initiating therapy; or confirmed PD on MK-3475
-safety of talimogene laherparepvec in combination with MK-3475; compared to MK-3475 alone; or following confirmed PD on MK-3475 alone
-incidence of anti-MK-3475 antibodies when MK-3475 is administered in combination with talimogene laherparepvec; alone or in combination with TVEC; or following confirmed PD on MK-3475 alone
-PK of MK-3475 when administered in combination with TVEC; or in combination with talimogene laherparepvec; or following confirmed PD on MK-3475 alone
-whether talimogene laherparepvec induces changes in PD-L1 expression by immunohistochemistry in injected and in non-injected lesions

Primary end point(s): Phase 1b:
- Incidence of DLT

Phase 2, Part 1:
- Confirmed ORR (CR+PR) by week 24 from the date of the first dose of MK-3475 in phase 2 part 1 (response evaluation by an investigator using modified immune-related Response Criteria [irRC])

Phase 2, Part 2:
- Confirmed ORR (CR+PR) by week 24 from the date of the first dose of MK-3475 in combination with talimogene laherparepvec in phase 2 part 2 (response evaluation by an investigator using modified irRC).

Main Objective: Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with MK-3475 in subjects with previously untreated, unresected, stage IIIB to IVM1c melanoma.

Phase 2, Part 1: To evaluate the efficacy, as assessed by the confirmed objective response rate (ORR) by week 24 of treatment with talimogene laherparepvec in combination with MK-3475, as
compared to MK-3475 alone.

Phase 2, Part 2: To evaluate the efficacy, as assessed by the confirmed ORR by week 24 of treatment with talimogene laherparepvec in combination with MK-3475 following progression on
MK-3475 alone in part 1 of phase 2.

Timepoint(s) of evaluation of this end point: Phase 1b:
The primary analysis will occur when the last subject enrolled in the phase 1b has had the opportunity to be on treatment for at least 6 weeks from the initial dosing of MK-3475.

Phase 2:
The timing of the primary analysis for part 1 of phase 2 will be when
all subjects have had the opportunity to complete 36 weeks of treatment.

The timing of the primary analysis for part 2 of phase 2 will be when all subjects who have confirmed progression by month 20 on MK-3475
alone in part 1 of phase 2 have had the opportunity to cross over to part 2 of phase 2 and complete 36 weeks of treatment.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: The clinical study report (CSR) will be written based on the results of the primary analysis of phase 2 (part 1 and part 2) and also include the results from the phase 1b and second-course (retreatment).

Secondary end point(s): Phase 1b:
- Confirmed ORR (CR+PR) by 24 weeks from the date of the first dose of MK-3475.
- BOR, DRR, DOR, PFS, and OS
- Ordinal categorical response score
- Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ? 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest).
- Incidence of anti-MK-3475 antibodies
- Descriptive statistics of trough and peak levels of MK-3475

Phase 2, Part 1:
- BOR, DRR, DOR, PFS, and OS
- Ordinal categorical response score and deep response rate (CR+Very Good Partial Response [VGPR])
-BOR, ordinal categorical response score, deep response rate, (CR+VGPR), DRR, DOR, PFS, and OS for PD-L1 negative subjects and PD-L1 positive subjects based on pre-treatment biopsy specimen.
- Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ? 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest.
- Incidence of anti-MK-3475 antibodies.
- Descriptive statistics of trough and peak levels of MK-3475.

Phase 2, Part 2:
- BOR, ordinal categorical response score, deep response rate (CR+VGPR), DRR, DOR, PFS and OS.
- Incidence of treatment-emergent and treatment-related adverse events (all AEs, grade ? 3 AEs, serious adverse events, fatal AEs, and AEs defined as events of interest).
- Incidence of anti-MK-3475 antibodies.
- Pharmacokinetic parameters for MK-3475.

Phase 1b and Phase 2:
- Changes in PD-L1 expression by immunohistochemistry (eg, negative to positive) that occur in injected lesions after starting talimogene laherparepvec in either subjects who are treatment-naïve (phase 1b) or those who have been receiving MK-3475 (part 2 of phase 2) and are PD-L1-negative prior to receiving talimogene laherparepvec.
- Changes in PD-L1 expression by immunohistochemistry (eg, negative to positive) that occur in non-injected lesions after starting talimogene laherparepvec in either subjects who are treatment-naïve (phase 1b) or those who have been receiving MK-3475 (part 2 of phase 2) and are PD-L1-negative prior to receiving talimogene laherparepvec.

Secondary ID(s)

20110265

2014-000185-22-SE

Source(s) of Monetary Support

Amgen Inc.

Merck Sharp and Dohme International GmbH

Ethics review

Status: Approved
Approval date: 28/10/2014
Contact: