Clinical Trial: NCT02453282 - My Cancer Genome

NCT02453282

Description:

This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type locally advanced or metastatic NSCLC

Related Conditions:

Non-Small Cell Lung Carcinoma

Recruiting Status:

Active, not recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT02453282

Trial Eligibility

Document

Title

Brief Title: Phase III Open Label First Line Therapy Study of MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC).
Official Title: A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy or MEDI4736 Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in First Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC) (MYSTIC)

Clinical Trial IDs

ORG STUDY ID: D419AC00001
NCT ID: NCT02453282

Conditions

Non-Small-Cell Lung Carcinoma NSCLC

Interventions

Drug	Synonyms	Arms
MEDI4736 (Durvalumab)		Monotherapy
MEDI4736 (Durvalumab)+Tremelimumab		Combination Therapy
Paclitaxel + Carboplatin	Platinum based Standard of Care Chemotherapy	Standard of Care
Gemcitabine + Cisplatin	Platinum based Standard of Care Chemotherapy	Standard of Care
Gemcitabine + Carboplatin	Platinum based Standard of Care Chemotherapy	Standard of Care
Pemetrexed + Cisplatin	Platinum based Standard of Care Chemotherapy	Standard of Care
Pemetrexed + Carboplatin	Platinum based Standard of Care Chemotherapy	Standard of Care
Tremelimumab		Combination Therapy

Purpose

Detailed Description

      Patients will be randomized in a 1:1:1 ratio to receive treatment with MEDI4736 +
      tremelimumab combination therapy, MEDI4736 monotherapy, or Standard of Care (SoC) therapy.

Trial Arms

Name	Type	Description	Interventions
Monotherapy	Experimental	PD-L1 monoclonal Antibody monotherapy.	MEDI4736 (Durvalumab)
Combination Therapy	Experimental	PD-L1+Tremelimumab combination therapy	MEDI4736 (Durvalumab)+Tremelimumab Tremelimumab
Standard of Care	Active Comparator	Standard of Care chemotherapy treatment	Paclitaxel + Carboplatin Gemcitabine + Cisplatin Gemcitabine + Carboplatin Pemetrexed + Cisplatin Pemetrexed + Carboplatin

Eligibility Criteria

        Inclusion Criteria:

        For inclusion in the study, patients should fulfill the following criteria:

          -  Aged at least 18 years

          -  Documented evidence of Stage IV NSCLC

          -  No sensitizing EGFR mutation or ALK rearrangement

          -  No prior chemotherapy or any other systemic therapy for recurrent/metastatic NSCLC

          -  World Health Organization (WHO) Performance Status of 0 or 1

        Exclusion Criteria:

        Patients should not enter the study if any of the following exclusion criteria are
        fulfilled:

          1. Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant

          2. Brain metastases or spinal cord compression unless asymptomatic, treated and stable
             (not requiring steroids)

          3. Prior exposure to Immunomodulatory therapy (IMT), including, but not limited to, other
             anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), anti-programmed cell death1
             (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti PD-L2 antibodies,
             excluding therapeutic anticancer vaccines

          4. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis or Crohn's disease]

Maximum Eligible Age:	130 Years
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Overall Survival (OS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs SoC Chemotherapy
Time Frame:	From baseline (Day 1, Week 0) until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Secondary Outcome Measures

Measure:	OS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab + Tremelimumab Vs Durvalumab Monotherapy
Time Frame:	From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Measure:	OS; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Measure:	OS; FAS Population
Time Frame:	From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Measure:	PFS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs Durvalumab Monotherapy
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). The PD was defined as at least a 20% increase in the sum of diameters of TLs and an absolute increase of at least 5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.

Measure:	PFS; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). The PD was defined as at least a 20% increase in the sum of diameters of TLs and an absolute increase of at least 5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.

Measure:	PFS; FAS Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The PFS per RECIST 1.1 using BICR assessments was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). The PD was defined as at least a 20% increase in the sum of diameters of TLs and an absolute increase of at least 5 mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.

Measure:	Objective Response Rate (ORR); PD-L1 (TC >=25%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The ORR per RECIST 1.1 using BICR assessments was defined as the percentage of participants with at least 1 visit response of Complete Response (CR) or Partial Response (PR). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	ORR; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The ORR per RECIST 1.1 using BICR assessments was defined as the percentage of participants with at least 1 visit response of CR or PR. The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	ORR; FAS Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The ORR per RECIST 1.1 using BICR assessments was defined as the percentage of participants with at least 1 visit response of CR or PR. The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	Duration of Response (DoR); PD-L1 (TC >=25%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The DoR per RECIST 1.1 using BICR assessments was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	DoR; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The DoR per RECIST 1.1 using BICR assessments was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	DoR; FAS Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
Safety Issue:
Description:	The DoR per RECIST 1.1 using BICR assessments was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). The CR was defined as disappearance of all TLs (any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of TLs (taking as reference the baseline sum of diameters as long as criteria for PD are not met).

Measure:	Percentage of Participants Alive and Progression Free at 12 Months (APF12); PD-L1 (TC >=25%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 12 months.
Safety Issue:
Description:	The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 using BICR assessments at 12 months after randomization. The PFS was calculated using the Kaplan-Meier technique.

Measure:	Percentage of Participants APF12; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 12 months.
Safety Issue:
Description:	The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 using BICR assessments at 12 months after randomization. The PFS was calculated using the Kaplan-Meier technique.

Measure:	Percentage of Participants APF12; FAS Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to 12 months.
Safety Issue:
Description:	The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 using BICR assessments at 12 months after randomization. The PFS was calculated using the Kaplan-Meier technique.

Measure:	Time From Randomization to Second Progression (PFS2); PD-L1 (TC >=25%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).
Safety Issue:
Description:	The PFS2 was defined as the time from the date of randomization to the earliest of the progression events (subsequent to that used for the primary variable PFS and excluding any confirmation of progression scans performed for first progression) or death (ie, date of PFS2 event or censoring - date of randomization + 1). The second progression event was determined by local standard clinical practice which may have included any of the following: objective radiological imaging, symptomatic progression, or death.

Measure:	PFS2; PD-L1 (TC >=1%) Analysis Set Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).
Safety Issue:
Description:	The PFS2 was defined as the time from the date of randomization to the earliest of the progression events (subsequent to that used for the primary variable PFS and excluding any confirmation of progression scans performed for first progression) or death (ie, date of PFS2 event or censoring - date of randomization + 1). The second progression event was determined by local standard clinical practice which may have included any of the following: objective radiological imaging, symptomatic progression, or death.

Measure:	PFS2; FAS Population
Time Frame:	Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).
Safety Issue:
Description:	The PFS2 was defined as the time from the date of randomization to the earliest of the progression events (subsequent to that used for the primary variable PFS and excluding any confirmation of progression scans performed for first progression) or death (ie, date of PFS2 event or censoring - date of randomization + 1). The second progression event was determined by local standard clinical practice which may have included any of the following: objective radiological imaging, symptomatic progression, or death.

Measure:	Change From Baseline in Disease-Related Symptoms as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) at 12 Months
Time Frame:	At baseline then every 4 weeks for the first 8 weeks relative to the date of randomization, then every 8 weeks until second progression/death, whichever comes first. Assessed up to 12 months.
Safety Issue:
Description:	Patient reported outcomes for 5 disease related symptoms was assessed using the EORTC QLQ-Core 30 (C30) items questionnaire (fatigue and appetite loss) and the EORTC QLQ-Lung Cancer module 13 (LC13) (dysponea, cough and chest pain). An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items with higher scores representing greater symptom severity. An improvement in symptoms were indicated by a negative change in score from baseline. A positive change in score from baseline indicated a deterioration of symptoms. A minimum clinically meaningful change is defined as an absolute change in the score from baseline of >=10.

Measure:	Serum Concentrations of Durvalumab
Time Frame:	Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, and at follow-up Month 3.
Safety Issue:
Description:	Blood samples were collected to determine the serum concentration of durvalumab.

Measure:	Serum Concentrations of Tremelimumab
Time Frame:	Pre-dose and within 1 hour after end of infusion at Week 0 and 12, and at follow-up Month 3.
Safety Issue:
Description:	Blood samples were collected to determine the serum concentration of tremelimumab.

Measure:	Maximum Serum Concentration at Steady State (Cmax_ss) of Durvalumab
Time Frame:	Within 1 hour after end of infusion on infusion day at Week 12.
Safety Issue:
Description:	Blood samples were collected to determine the Cmax_ss of durvalumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Measure:	Cmax_ss of Tremelimumab
Time Frame:	Within 1 hour after end of infusion on infusion day at Week 12.
Safety Issue:
Description:	Blood samples were collected to determine the Cmax_ss of tremelimumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Measure:	Trough Serum Concentration at Steady State (Ctrough_ss) of Durvalumab
Time Frame:	Pre-dose at Week 12.
Safety Issue:
Description:	Blood samples were collected to determine the Ctrough_ss of durvalumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Measure:	Ctrough_ss of Tremelimumab
Time Frame:	Pre-dose at Week 12.
Safety Issue:
Description:	Blood samples were collected to determine the Ctrough_ss of tremelimumab. Steady state was defined as Cycle 4 (Week 12). PK parameters were determined using standard non-compartmental methods.

Measure:	Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab
Time Frame:	At Weeks 0, 12, and 24; 3 and 6 months after last dose of study treatment.
Safety Issue:
Description:	Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. Tiered analysis was performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples were employed. Immunogenicity results were analyzed by summarizing the number of participants who developed detectable ADAs against durvalumab. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

Measure:	Number of Participants With ADA Response to Tremelimumab
Time Frame:	At Weeks 0 and 12; 3 and 6 months after last dose of study treatment.
Safety Issue:
Description:	Blood samples were measured for the presence of ADAs and ADA-nAb for tremelimumab using validated assays. Tiered analysis was performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples were employed. Immunogenicity results were analyzed by summarizing the number of participants who developed detectable ADAs against tremelimumab. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	AstraZeneca

Trial Keywords

NSCLC, PD-L1, MEDI4736, Tremelimumab, PFS, OS

Last Updated

July 7, 2021

Clinical Trials /

Phase III Open Label First Line Therapy Study of MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non Small-Cell Lung Cancer (NSCLC).