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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03484923
Registration number
NCT03484923
Ethics application status
Date submitted
26/03/2018
Date registered
2/04/2018
Date last updated
18/01/2024
Titles & IDs
Public title
Study of Efficacy and Safety of Novel Spartalizumab Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma
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Scientific title
A Randomized, Open-label, Phase II Open Platform Study Evaluating the Efficacy and Safety of Novel Spartalizumab (PDR001) Combinations in Previously Treated Unresectable or Metastatic Melanoma
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Secondary ID [1]
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2018-000610-38
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Secondary ID [2]
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CPDR001J2201
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Universal Trial Number (UTN)
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Trial acronym
PLATforM
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Melanoma
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Condition category
Condition code
Cancer
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Malignant melanoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - PDR001
Treatment: Drugs - LAG525
Treatment: Drugs - INC280
Treatment: Drugs - ACZ885
Treatment: Drugs - LEE011
Experimental: Arm 1: LAG525 + PDR001 (randomized section) - Participnats randomized to receive LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks
Experimental: Arm 2: INC280+PDR001 (randomized section) - Participants randomized to receive INC280 orally at a dosage of 400 mg twice daily, in combination with PDR001 intravenously at a dosage of 400 mg every 4 weeks
Experimental: Arm 3: ACZ885 + PDR001 (randomized section) - Participants randomized to receive to receive ACZ885 at a dosage of 300 mg administered subcutaneously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks
Experimental: Arm 4: LEE011 + PDR001 (randomized section) - Participants randomized to receive LEE011 orally at a dosage of 600 mg once daily on Days 1-21 of a 28-day cycle, in combination with PDR001 intravenously at a dosage of 400 mg every 4 weeks
Experimental: Arm 1A: LAG525 + PDR001 (non-randomized section) - LAG-3 positive participants received LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks
Treatment: Drugs: PDR001
400 mg of PDR001 administered every 4 weeks intravenously
Treatment: Drugs: LAG525
600 mg of LAG525 administered every 4 weeks intravenously
Treatment: Drugs: INC280
400 mg of INC280 administered twice daily orally
Treatment: Drugs: ACZ885
200 mg of ACZ885 administered every 4 weeks subcutaneosuly
Treatment: Drugs: LEE011
600 mg of LEE011 orally taken once daily on Days 1-21 of a 28-day cycle
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Response Rate (ORR)
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Assessment method [1]
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ORR defined as the percentage of patients with a best overall response of either confirmed complete response (CR) or partial response (PR) as per local review by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and assessed by computed tomography (CT)/ magnetic resonance imaging (MRI).
CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
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Timepoint [1]
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Up to 49 months (randomized section) and 18 months (non-randomized section)
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Secondary outcome [1]
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Duration of Response (DOR)
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Assessment method [1]
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DOR defined as the time from date of first documented CR or PR to date of first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment.
CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
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Timepoint [1]
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From first documented response to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized part) and 18 months (non-randomized part)
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Secondary outcome [2]
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Overall Survival (OS)
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Assessment method [2]
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OS was defined as the time from date of randomization (or date of first dose of study treatment in non-randomized part) to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method, and the medians and 95% confidence intervals of the medians were presented.
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Timepoint [2]
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From randomization (or start of treatment for non-randomized section) to death due to any cause, assessed up to 49 months (randomized section) and 24 months (non-randomized section)
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Secondary outcome [3]
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Progression Free Survival (PFS)
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Assessment method [3]
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PFS was defined as the time between the date of randomization (or date of first dose of study treatment in non-randomized section) to the date of event defined as the first documented disease progression (as per local review by RECIST v1.1 and assessed by CT/MRI) or death due to any cause. If a subject had not had an event before leaving study or initiation of subsequent anticancer therapy, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using the Kaplan-Meier method, medians and 95% confidence interval of the medians were presented.
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Timepoint [3]
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From randomization (or start of treatment for non-randomized section) to disease progression or death due to any cause, whichever occurs first, assessed up to 49 months (randomized section) and 18 months (non-randomized section)
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Secondary outcome [4]
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Disease Control Rate (DCR)
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Assessment method [4]
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DCR was defined as the percentage of participants with best overall response of CR, PR or stable disease (SD) (as per local review by RECIST v1.1 and assessed by CT/MRI).
CR:Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
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Timepoint [4]
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Up to 49 months (randomized section) and 18 months (non-randomized section)
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Secondary outcome [5]
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Percentage of Participants With PDR001 Anti-drug Antibodies (ADA) Positive Result at Baseline
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Assessment method [5]
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Percentage of participants who had a PDR001 ADA positive result at baseline.
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Timepoint [5]
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At Baseline
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Secondary outcome [6]
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Percentage of Participants With LAG525 Anti-drug Antibodies (ADA) Positive Result at Baseline
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Assessment method [6]
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Percentage of participants who had a LAG525 ADA positive result at baseline. Only applicable for participants enrolled in Arm 1 and Arm 1A.
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Timepoint [6]
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At Baseline
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Secondary outcome [7]
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Percentage of Participants With ACZ885 Anti-drug Antibodies (ADA) Positive Result at Baseline
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Assessment method [7]
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Percentage of participants who had an ACZ885 ADA positive result at baseline. Only applicable for subjects enrolled in Arm 3.
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Timepoint [7]
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At Baseline
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Secondary outcome [8]
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Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for PDR001
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Assessment method [8]
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Percentage of participants who tested positive for treatment-induced ADA for PDR001 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for PDR001 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment).
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Timepoint [8]
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Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT), EOT, and 30 and 150 days post-EOT (assessed up to 49 months randomized section and 24 months non-randomized section). Cycle= 28 days
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Secondary outcome [9]
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Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for LAG525
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Assessment method [9]
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Percentage of participants who tested positive for treatment-induced ADA for LAG525 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for LAG525 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 1 and Arm 1A.
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Timepoint [9]
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Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 49 months in the randomized section and 18 months in the non-randomized section). Cycle= 28 days
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Secondary outcome [10]
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Percentage of Participants Who Were Treatment-induced ADA Positive and Treatment-boosted ADA Positive for ACZ885
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Assessment method [10]
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Percentage of participants who tested positive for treatment-induced ADA for ACZ885 (subjects with ADA-negative sample at baseline with at least one post-baseline ADA positive sample) as well as treatment-boosted ADA for ACZ885 (subjects with baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment). Only applicable for subjects enrolled in Arm 3.
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Timepoint [10]
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Pre-infusion on Day 1 of Cycle 1, 2, 3, 4, 5, 6 and thereafter every 3 cycles until end of treatment (EOT) and EOT (assessed up to 40 months). Cycle= 28 days
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Secondary outcome [11]
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Percentage of Participants With a Favorable Biomarker Profile (pFBP)
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Assessment method [11]
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Biomarker parameters included: 1) number of tumor infiltrating T cells (TIL), 2) activation level of TIL, and 3) changes in immune response gene expression signatures. For the number of TILs, an increase in tumoral CD8+ cell numbers compared to baseline was considered favorable. The activation level of TIL was assessed by the percentage of tumoral CD8+ cells expressing GzmB (a marker for cytotoxic activity) or Ki67 (a marker for cell proliferation), where an increase in either GZMB+/CD8+ or KI67+/CD8+ post-baseline was considered favorable. Changes in immune response gene expression signatures were evaluated by the levels in T-cell inflamed signature (TIS), where an increase from baseline was considered favorable.
To be categorized as having a pFBP, a subject must meet the favorable criteria for at least two of the three biomarker parameters. The percentage of participants with pFBP was assessed.
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Timepoint [11]
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Baseline and after 3-4 weeks of treatment
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Eligibility
Key inclusion criteria
Key inclusion criteria for Arm 1, 2, 3, 4:
- Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma
using AJCC edition 8.
- Previously treated for unresectable or metastatic melanoma:
- Subjects with V600BRAF wild-type disease had to have received prior systemic
therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1.
Additionally, subjects may have received anti-CTLA-4 as a single agent or in
combination with anti-PD-1/PD-L1, irrespective of the sequence. No additional
systemic treatment was allowed for advanced or metastatic melanoma.
A maximum of two prior lines of systemic therapies for unresectable or metastatic melanoma
were allowed.
The last dose of prior therapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4) had to have been
received more than four weeks before randomization.
- Subjects with V600BRAF mutant disease had to have received prior systemic therapy for
unresectable or metastatic melanoma with anti-PD-1/PD-L1 and V600BRAF inhibitor.
Additionally, subjects may have received anti-CTLA-4 as a single agent or in
combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination with V600BRAF
inhibitor or as a single agent), irrespective of the sequence. No additional systemic
treatment was allowed for advanced or metastatic melanoma.
- A maximum of three prior lines of systemic therapies for unresectable or metastatic
melanoma were allowed.
- The last dose of prior therapy had to have been received more than 4 weeks (for
anti-PD-1, anti-PD-L1, or anti-CTLA-4) or more than 2 weeks (for V600BRAF or MEK
inhibitor) prior to randomization.
- All subjects (with V600BRAF wild-type disease and with V600BRAF mutant disease) had to
have documented disease progression as per RECIST v1.1 while on/after the last therapy
received prior to study entry and while on/after treatment with anti-PD1/PD-L1. The
last progression had to have occurred within 12 weeks prior to randomization in the
study.
- ECOG performance status 0-2.
- At least one measurable lesion per RECIST v1.1.
- At least one lesion, suitable for sequential mandatory tumor biopsies (screening
and on-treatment) in accordance with the biopsy guidelines specified in the
protocol. The same lesion had to be biopsied sequentially.
- Screening tumor biopsy had to fulfill the tissue quality criteria outlined in the
protocol, as assessed by a local pathologist.
Key inclusion criteria for Arm 1A:
- Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma
according to AJCC Edition 8.
- Previously treated for unresectable or metastatic melanoma:
- All subjects had to have received anti-PD-1 checkpoint inhibitor therapy (i.e.,
pembrolizumab or nivolumab) either as monotherapy or in combination with
ipilimumab as the last systemic therapy prior to enrollment and had to have
confirmed disease progression as per RECIST v1.1 (confirmed on a subsequent scan,
which could be the scan performed during screening) while on or after this
therapy prior to enrollment.
- Subjects with V600BRAF wild-type disease had to have received no more than 2
prior systemic therapies, including prior anti-PD-1/PD-L1 (as monotherapy or in
combination with ipilimumab).
- Subjects with V600BRAF mutant disease had to have received no more than 3 prior
systemic therapies, including anti-PD-1/PD-L1 (as monotherapy or in combination
with ipilimumab) and V600BRAF inhibitor (as monotherapy or in combination with a
MEK inhibitor).
- The last dose of anti-PD-1-based therapy had to have been received more than four
weeks prior to the first dose of study treatment.
- The last documented disease progression had to have occurred within 12 weeks
prior to the first dose of study treatment.
- No additional systemic treatment was allowed for advanced or metastatic melanoma
(this included, for example, tumor-infiltrating lymphocyte therapy).
- ECOG performance status 0-1.
- At least one measurable lesion per RECIST v1.1.
- Subjects had to have a baseline tumor sample that was positive for LAG-3 per central
assessment.
Key exclusion criteria common to all combination arms:
- Subjects with uveal or mucosal melanoma.
- Presence of clinically active or unstable brain metastasis at the time of screening.
- Use of any live vaccines against infectious diseases within 3 months before
randomization/enrollment.
- Active infection requiring systemic antibiotic therapy at the time of
randomization/enrollment.
- Subjects with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization/enrollment. Inhaled or topical steroids, and adrenal replacement
steroid doses >10 mg daily prednisone equivalent, were permitted in the absence of
active autoimmune disease.
- Active, known or suspected autoimmune disease or a documented history of autoimmune
disease.
- Prior allogenic bone marrow or solid organ transplant.
- History of known hypersensitivity to any of the investigational drugs used in this
study.
- Malignant disease, other than that being treated in this study.
- Prior systemic therapy for unresectable or metastatic melanoma with any
investigational agent or with any other agent except anti-PD-1/PD-L1 and anti-CTLA-4
(and V600BRAF and MEK inhibitors if the subject has V600BRAF mutant disease). Prior
neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before
the start of the study treatment.
- Medical history or current diagnosis of myocarditis.
- Cardiac Troponin T (or Troponin I) level > 2 x ULN at screening.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
10/09/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
30/12/2022
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Sample size
Target
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Accrual to date
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Final
196
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Novartis Investigative Site - North Sydney
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Recruitment hospital [2]
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Novartis Investigative Site - Westmead
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Recruitment postcode(s) [1]
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2060 - North Sydney
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Recruitment postcode(s) [2]
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2145 - Westmead
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Massachusetts
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Country [3]
0
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United States of America
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State/province [3]
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New York
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Country [4]
0
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United States of America
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State/province [4]
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Pennsylvania
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Country [5]
0
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Canada
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State/province [5]
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Ontario
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Country [6]
0
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Canada
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State/province [6]
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Quebec
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Country [7]
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France
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State/province [7]
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Marseille
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Country [8]
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France
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State/province [8]
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Paris 10
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Country [9]
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France
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State/province [9]
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Villejuif
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Country [10]
0
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Germany
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State/province [10]
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Dresden
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Country [11]
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Germany
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State/province [11]
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Essen
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Country [12]
0
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Germany
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State/province [12]
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Hamburg
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Country [13]
0
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Germany
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State/province [13]
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Kiel
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Country [14]
0
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Germany
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State/province [14]
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Muenchen
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Country [15]
0
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Italy
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State/province [15]
0
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BG
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Country [16]
0
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Italy
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State/province [16]
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MI
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Country [17]
0
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Italy
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State/province [17]
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Napoli
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Country [18]
0
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Netherlands
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State/province [18]
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Amsterdam
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Country [19]
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Netherlands
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State/province [19]
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Rotterdam
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Country [20]
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Spain
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State/province [20]
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Catalunya
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Country [21]
0
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Spain
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State/province [21]
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Madrid
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Country [22]
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Switzerland
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State/province [22]
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Zuerich
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Country [23]
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United Kingdom
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State/province [23]
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Middlesex
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Country [24]
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United Kingdom
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State/province [24]
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London
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Country [25]
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United Kingdom
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State/province [25]
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Manchester
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary purpose of this study is to evaluate the efficacy of novel spartalizumab (PDR001)
combinations in previously treated unresectable or metastatic melanoma
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03484923
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03484923
Download to PDF