Details

Details

Title A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265) - is now open to accrual. Phase 1b is complete and we will only be participating in Phase 3

IRB AMGN1615

CC 16-330

Hospital Main Campus

Stage Stage 3, Stage 4

Phase Phase 1, Phase 2, Phase 3

Disease Melanoma

Drug Pembrolizumab, Talimogene Laherparepvec

Description

Description

Primary Objectives:
  • Phase 1b: To evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in subjects with previously untreated, unresectable, stage IIIB to IVM1c melanoma.
  • Phase 3: To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded central review using modified Response Evaluation Criteria in Solid Tumors 1.1 [RECIST]) and overall survival (OS).
Secondary Objectives:
  • Phase 1b:
    • To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab as assessed by:
      • Confirmed objective response rate (ORR), best overall response (BOR), durable response rate (DRR), duration of response (DOR), disease control rate (DCR), and PFS (response evaluation by investigator using modified Immune-related Response Criteria [irRC])
      • OS
    • To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as assessed by incidence of treatment-emergent and treatment-related adverse events (AEs).
  • Phase 3:
    • To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by:
      • ORR, BOR, DRR, DOR, DCR (response evaluation by blinded central review assessed modified RECIST 1.1 and investigator-assessed irRC-RECIST)
      • PFS (response evaluation by investigator-assessed irRC-RECIST)
      • Landmark survival by year
    • To evaluate the safety of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by incidence of treatment-emergent and treatment-related AEs.
    • To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in subjects whose tumors are either programmed cell death-1 ligand 1 (PD-L1)-negative or PD-L1-positive prior to initiating therapy (as assessed by the ORR, BOR, PFS, DRR, DOR, DCR [response evaluation by blinded central review assessed modified RECIST 1.1 and investigator-assessed irRC-RECIST], OS, and landmark survival by year).
    • To evaluate patient reported outcomes (PRO) in phase 3 as assessed by the EuroQoL-5D (EQ-5D) and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)
Inclusion Criteria

Inclusion Criteria

  1. Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
  2. Male or female age ≥ 18 years at the time of informed consent
  3. Histologically confirmed diagnosis of melanoma
  4. Disease stage: Subject with unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c melanoma
  5. Candidate for intralesional therapy defined as either one of the following:
    • at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion ≥ 10 mm in longest diameter
    • multiple injectable melanoma lesions that in aggregate have a longest diameter of ≥ 10 mm injectable disease
  6. ECOG performance status of 0 or 1
  7. Adequate organ function determined within 14 days prior to enrollment, defined as follows:
    • ANC ≥ 1.5 x 109/L
    • platelet count ≥ 100 x 109/L
    • hemoglobin ≥ 9 g/dL (without need for hematopoietic growth factor or transfusion support)
    • serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: Creatinine clearance need not be determined if the baseline serum creatinine is within normal limits. Creatinine clearance should be calculated per institutional standard).
    • serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total bilirubin level > 1.5 x ULN
    • aspartate aminotransferase (AST) ≤ 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases
    • alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN for subject with liver metastases
    • international normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) is within therapeutic range of intended use of anticoagulants
    • PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants
  8. 110 Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

    9. Inclusion Criteria Specific to Phase 1b

  9. Prior therapy for melanoma inclusion requirement: Treatment na�ve: Must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma. Note: Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to radiotherapy, interferon, limb infusion/perfusion, or use of investigational agents in the adjuvant setting). However, if the subject received a course of adjuvant therapy, the subject must have ended therapy at least 3 months prior to enrollment. If adjuvant therapy was not completed due to intolerance, the subject must have ended therapy at least 3 months prior to enrollment. No prior pembrolizumab, other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, ipilimumab, other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways is allowed, even if given in the adjuvant setting.
  10. Measurable disease: defined as either one of the following:
    • at least 1 visceral or nodal/soft tissue melanoma lesion (including lymph nodes) that can be accurately and serially measured in at least 2 dimensions and for which the longest diameter is ≥ 10 mm as measured by CT scan or MRI
    • at least 1 superficial cutaneous or subcutaneous melanoma lesion that can be accurately and serially measured in at least 1 dimension and for which the longest diameter is ≥ 10 mm as measured by calipers

    11. Inclusion Criteria Specific to Phase 3

  11. BRAF wild-type: Subjects with BRAF wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma. BRAF mutation: Subjects with BRAF mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with MEK inhibitor as their only prior line of systemic therapy are eligible for this study. However, the subject must have ended BRAF inhibitor therapy either alone or in combination with MEK inhibitor at least 14 days prior to enrollment and have adequately recovered from any treatment-related adverse events (ie, ≤ Grade 1 or baseline). Note: Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to radiotherapy, interferon, limb infusion/perfusion, ipilimumab, or use of investigational agents in the adjuvant setting). However, the subject must have ended therapy at least 28 days prior to enrollment. No prior anti-CD137, ipilimumab or other CTLA-4 inhibitor, talimogene laherparepvec, tumor vaccine, or any other oncolytic viruses or drugs specifically targeting T-cell co-stimulation or checkpoint pathways are allowed in a non-adjuvant setting. No prior pembrolizumab or any other inhibitor of PD-1, PD-L1 or PD-L2 are allowed in any setting.
  12. Measurable disease defined as:
    • at least 1 visceral or nodal/soft tissue melanoma lesion that can be accurately and serially measured in at least 1 dimension and for which the longest diameter is ≥ 10 mm as measured by CT scan or MRI. Lymph nodes must measure ≥ 15 mm in their short axis to be considered measurable by CT scan or MRI
  13. Subject has a tumor sample (archival sample obtained within 3 months prior to day 1 and no systemic therapy given 3 months prior biopsy or newly obtained biopsy) that is submitted for PD-L1 assessment prior to randomization. Subject must submit the tumor sample during screening for PD-L1 expression testing at acentral laboratory. Subjects will be eligible to participate regardless of the level of PD-L1 expression. Subjects with an unevaluable archival sample may obtain a new biopsy and subjects with an unevaluable newly obtained biopsy may undergo re-biopsy at the discretion of the investigator

Exclusion Criteria

Exclusion Criteria

  1. Clinically active cerebral melanoma metastases. Subjects with up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression, and have not required steroids, for at least 2 months prior to enrollment.
  2. Primary uveal or mucosal melanoma
  3. History or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia)
  4. History of other malignancy within the past 3 years with the following exceptions:
    • malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for ≤ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
    • adequately treated non-melanoma skin cancer without evidence of disease at the time of enrollment
    • adequately treated cervical carcinoma in situ without evidence of disease at the time of enrollment
    • adequately treated breast ductal carcinoma in situ without evidence of disease at the time of enrollment
    • prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment
    • adequately treated superficial or in-situ carcinoma of the bladder without evidence of disease at the time of enrollment
  5. Prior therapy with talimogene laherparepvec or any other oncolytic viruses
  6. Prior therapy with tumor vaccine
  7. Prior therapy with pembrolizumab or any other inhibitor of PD-1, PD-L1 or PD-L2. Prior therapy in a non-adjuvant setting with anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  8. Prior monoclonal antibody therapy within 28 days prior to enrollment or who has not recovered (ie, ≤ grade 1 or at baseline) from adverse events due to agents administered more than 28 days earlier
  9. Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study
  10. Expected to require other cancer therapy while on study with the exception of local radiation treatment to the site of bone and other metastasis for palliative pain management
  11. Other investigational procedures while participating in this study are excluded.
  12. History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  13. Evidence of clinically significant immunosuppression such as the following:
    • diagnosis of immunodeficiency
    • concurrent opportunistic infection
    • receiving systemic immunosuppressive therapy (> 2 weeks) or within 7 days prior to the first dose of study treatment, including oral steroid doses > 10 mg/day of prednisone or equivalent except for management of adverse events and central nervous system (CNS) metastases during the course of the study. Subjects that require intermittent use of bronchodilators or local steroid injection will not be excluded from the study.
  14. Active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis)
  15. Require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use
  16. Known human immunodeficiency virus (HIV) disease
  17. Known acute or chronic hepatitis B or hepatitis C infection
  18. Received live vaccine within 28 days prior to enrollment
  19. Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec or 4 months after the last dose of pembrolizumab, whichever is later
  20. Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec or 4 months after the last dose of pembrolizumab, whichever is later. Note: Women not of childbearing potential are defined as:
    • postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.) OR
    • have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR
    • has a congenital or acquired condition that prevents childbearing. Note: Acceptable methods of effective contraception are defined in the informed consent form. Where required by local laws and regulations, additional country-specific contraception requirements may be outlined in a country-specific protocol supplement at the end of the Appendix Section of protocol.
  21. Male subject who is unwilling to use acceptable method of effective contraception during pembrolizumab treatment and through 4 months after the last dose of pembrolizumab. For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). Note: Acceptable methods of effective contraception are defined in the informed consent form. Additional country-specific contraception requirements may be defined in a country-specific protocol supplement at the end of the Appendix Section of protocol as required by local laws and regulations.
  22. Subject has known sensitivity to any of the products or components to be administered during dosing
  23. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge
  24. History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
  25. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved in the this trial, unless prospective institutional review board (IRB)/independent ethics committee (IEC) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
  26. Sexually active subject who is unwilling to use a barrier method (male or female condom) to avoid potential viral transmission during sexual contact during and within 30 days after treatment with talimogene laherparepvec.
  27. Subject who is unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications (immunosuppressed individuals, HIV-positive individuals, pregnant women, or children under the age of 1 year) during talimogene laherparepvec treatment and through 28 days after the last dose of talimogene laherparepvec
  28. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease.)
  29. Has a known history of active Bacillus tuberculosis