Talimogene Laherparepvec With Pembrolizumab for Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY232 / KEYNOTE-137)

Phase 1

Completed

Conditions: Carcinoma of the Head and Neck

Interventions: Drug: Talimogene Laherparepvec
Biological: Pembrolizumab

Registration Number: NCT02626000

Lead Sponsor: Amgen

Brief Summary: The primary objective of this study was to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Detailed Description: This is a phase 1b/3, multicenter, clinical trial conducted in 2 parts (phase 1b and phase 3). In phase 1b talimogene laherparepvec is to be administered in combination with pembrolizumab to adults with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Dose limiting toxicity (DLT) is to be evaluated based on the first 18 DLT-evaluable participants. An expansion cohort of up to an additional 22 treated patients could be enrolled to further evaluate the safety and to estimate the efficacy of the combination of talimogene laherparepvec with pembrolizumab and to support a decision to initiate the phase 3 part of the study. The phase 3 part of the study was designed as a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, as assessed by overall survival, of treatment with talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in adults with recurrent or metastatic SCCHN, however, a decision was made not to proceed to the phase 3 part of the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Talimogene Laherparepvec + Pembrolizumab	Pembrolizumab	Talimogene laherparepvec is administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 3 weeks after the initial dose and every 3 weeks (Q3W) thereafter. Pembrolizumab is administered by intravenous infusion at a dose of 200 mg Q3W after the initial dose. Participants are treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.
Talimogene Laherparepvec + Pembrolizumab	Talimogene Laherparepvec	Talimogene laherparepvec is administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 3 weeks after the initial dose and every 3 weeks (Q3W) thereafter. Pembrolizumab is administered by intravenous infusion at a dose of 200 mg Q3W after the initial dose. Participants are treated until complete response, no injectable lesions, confirmed disease progression, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Dose Limiting Toxicity (DLT)	First 6 weeks after the initial administration of talimogene laherparepvec and pembrolizumab in combination	The following toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.0) were considered DLTs if judged by the investigator to be related to either study drug: * grade 4 non-hematologic (non-laboratory) toxicity * ≥ grade 3 pneumonitis * grade 3 non-hematologic toxicity for \> 3 days with optimal supportive care * grade 3 fatigue was not classified as DLT, regardless of duration * any ≥ grade 3 non-hematologic laboratory value if: * medical intervention was required, * the abnormality led to hospitalization, or * the abnormality persisted at ≥ grade 3 for \> 1 week unless deemed not clinically important by investigator and sponsor * grade 3 or 4 febrile neutropenia * thrombocytopenia \< 25 x 10⁹/L associated with bleeding event requiring intervention * serious herpetic event: herpetic encephalitis, encephalomyelitis, or disseminated herpetic infection * grade 5 toxicity * other intolerable toxicity leading to permanent discontinuation of either study drug.

Secondary Outcome Measures

Name	Time	Method
Complete Response Rate	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Complete response rate (iCRR) was defined as the percentage of participants with a best overall response of complete response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Analyses are presented below for both the unconfirmed and confirmed results.
Objective Response Rate	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Objective response rate was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required. Analyses are presented below for both the unconfirmed and confirmed results.
Disease Control Rate	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Disease control rate (iDCR) was defined as the percentage of participants with a best overall response of iCR or iPR or iSD assessed by the investigator using irRECIST. Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required. Stable disease (iSD): Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD. Analyses are presented below for both the unconfirmed and confirmed results.
Number of Participants With Adverse Events	From first dose of study drug to 30 days after last dose; the median (range) duration of treatment was 5.6 (0.1 to 75.3) weeks for talimogene laherparepvec and 6.1 (0.1, 105.3) weeks for pembrolizumab.	The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and based on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. A serious adverse event is an AE that met at least 1 of the following serious criteria: * fatal * life threatening * required in-patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event.
Best Overall Confirmed Response	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Best overall visit response of iCR, iPR, stable disease (iSD), progressive disease (iPD) or unevaluable (iUE) based on investigator assessment using irRECIST. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new). Any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. iPR: Decrease in tumor size ≥ 30% relative to baseline. iPD: Increase in tumor size ≥ 20% and at least 5 mm absolute increase compared to nadir or qualitative worsening of non-target lesions or a new lesion. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD. iUE: Any baseline lesion which was not assessed or was unable to be evaluated leading to an inability to determine the status of that particular tumor. Not Done: Radiographic imaging was not performed to evaluate the response. iCR, iPR, and iPD required confirmation by a consecutive assessment at least 4 weeks after first documentation.
Progression Free Survival	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Progression-free survival (iPFS) per irRECIST was defined as the interval from first dose to the earlier of a participant overall response of iPD or death from any cause; otherwise, iPFS was censored at the last evaluable tumor assessment. The initial date of an iPD that was consecutively confirmed was used.
Overall Survival	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Overall survival (OS) was defined as the interval from first dose to the event of death from any cause; otherwise, OS was censored at the date the participant was last known to be alive.
Duration of Confirmed Response	Up to the primary analysis data cutoff date of 02 November 2017; median (minimum, maximum) time on follow-up was 14.36 (1.4, 67.0) weeks.	Duration of response (iDOR) per irRECIST was defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of a participant overall response of iPD or death. Participants who did not end their response at the time of analysis were censored at their last evaluable tumor assessment.