Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies

Phase 2TerminatedNCT02608268

Novartis Pharmaceuticals252 enrolled

Overview

The purpose of this first-in-human study of MBG453 was to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of MBG453 administered i.v. as a single agent or in combination with PDR001 or decitabine in adult patients with advanced solid tumors

This study was a first in human (FIH), open-label, Phase I-Ib/II, multi-center study which consisted of a Phase I dose escalation part of sabatolimab (MBG453) as single agent, and a Phase Ib dose escalation part of sabatolimab in combination with spartalizumab (PDR001) that commenced after two cohorts in the dose escalation with single agent were completed. Once the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of sabatolimab as single agent and in combination with spartalizumab was achieved, a dose ranging part and a Phase II part started. • Phase I dose escalation part (sabatolimab single agent): In the Phase I part of the study, cohorts of subjects were treated with sabatolimab as single agent either every 2 weeks (Q2W) or every 4 weeks (Q4W) until the MTD was reached or a lower RP2D was established. The sabatolimab single agent dose escalation part in Japan ran separately in order to ensure that the safety and pharmacokinetics (PK) profiles of single-agent sabatolimab are adequately characterized in Japanese patients. If the recommended dose of single agent sabatolimab in Japanese patients was the same as in the rest of the world (ROW) patients, then patients enrolled in Japan were to be recruited into the other parts of the study. • Phase Ib dose escalation part (sabatolimab in combination with spartalizumab): The combination Phase Ib part of the study was to be commenced after at least two cohorts of sabatolimab as single agent were completed, and safety data suggested acceptable toxicity for subjects to begin treatment in combination. Following identification of the MTD/RP2D for the combination of sabatolimab and spartalizumab with a Q2W dosing schedule, a further dose escalation was planned to identify the MTD/RP2D with a Q4W dosing schedule. The sabatolimab in combination with decitabine treatment arm (Phase Ib) was not opened for enrollment. * Dose ranging part: During the dose ranging part various dose levels of single agent sabatolimab were tested to better understand the safety, tolerability and PK. * Phase II part (sabatolimab in combination with spartalizumab): Once the MTD and/or RP2D were declared for sabatolimab in combination with spartalizumab, additional subjects were enrolled in the Phase II part in the selected indications (melanoma and non-small cell lung carcinoma) in order to assess the preliminary anti-tumor activity. The Phase II single agent sabatolimab treatment arm was not opened for enrollment.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

252

Conditions

Advanced Malignancies

Interventions

MBG453DRUG

Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).

PDR001DRUG

Anti-human PD-1 monoclonal antibody. PDR001 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W).

DecitabineDRUG

commercially available chemotherapy

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically documented advanced or metastatic solid tumors. * Phase I-Ib part (including dose ranging part): Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease as determined by RECIST v1.1, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists and who did not receive prior anti-PD-1/PD-L1 treatment. * Phase II part (MBG453 single agent): Patients with advanced/metastatic solid tumors in the indication in which at least one confirmed PR or CR was seen during the dose escalation phase I part. Patients must have measurable disease as determined by RECIST v1.1, have progressed despite standard therapy or be intolerant to standard therapy. * Phase II part (MBG453 in combination PDR001): Patients with advanced/metastatic tumors in the below selected indications, with at least one measurable lesion as determined by RECIST v1.1, who have received standard therapy and are intolerant of standard therapy or have progressed following their last prior therapy.: * Melanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated) * Non small cell lung cancer (anti-PD-1/PD-L1 therapy naïve or pre-treated) * Renal Cell Carcinoma (anti-PD-1/PD-L1 therapy naïve or pre-treated) * Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/baseline, and during therapy on the study. * For MBG453 in combination with decitabine: anti-PD-1/PD-L1 therapy naïve SCLC patients who have failed no more than two lines of standard chemotherapy including topotecan Exclusion Criteria: * Presence of symptomatic central nervous system metastases. * History of severe hypersensitivity reactions to other monoclonal antibodies. * Human Immunodeficiency Virus, Hepatitis B Virus or Hepatitis C Virus infection. * Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids. * Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent). * Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment. * Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway. * Participation in an interventional, investigational non-immunotherapy study within 2 weeks of the first dose of study treatment. * Prior participation in an interventional, investigational cancer vaccine or immunotherapy study except for an anti-PD-1/PD-L1 study. * For MBG453 in combination with decitabine: Hypersensitivity to decitabine or to any of the excipients, listed in decitabine country specific label

Locations (14)

Sidney Kimmel CCC At JH Sidney Kimmel CCC

Baltimore, Maryland, United States

Dana Farber Cancer Institute DFCI - Brookline

Boston, Massachusetts, United States

UT M.D Anderson Cancer Center

Houston, Texas, United States

Outcomes

Primary Outcomes

Phase I-Ib and Dose Ranging Part: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period

Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.

Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 2 years for sabatolimab and 5 years for sabatolimab in combination with spartalizumab

Phase I-Ib: Number of Participants With Dose-Limiting Toxicities (DLTs)

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first cycle of treatment with sabatolimab as single agent or in the first two cycles of treatment when sabatolimab is given in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 28 days.

Time frame: 28 days (sabatolimab single agent) and 56 days (sabatolimab+spartalizumab)

Phase I-Ib and Dose Ranging Part: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab

Number of participants with at least one dose reduction of sabatolimab and number of participants with at least one dose interruption of sabatolimab.

Time frame: From first dose of study medication up to last dose, with a maximum duration of 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Best Overall Response (BOR) Per RECIST v1.1

BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal 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 diameters of all target lesions, taking as reference the baseline sum of diameters; PD= At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression; NCRNPD: Persistence of one or more non-target lesions. Number of participants in each category is reported in the table.

Time frame: From start of treatment until end of treatment, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Progression-Free Survival (PFS) Per RECIST v1.1

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was analyzed using Kaplan-Meier estimates.

Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Duration of Response (DOR) Per RECIST v1.1

DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment according to RECIST v1.1. DOR is defined as the time from the date of first documented response to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, duration was censored at the date of last adequate tumor assessment. According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.

Time frame: From first documented response to first documented disease progression or death due to underlying cancer, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Overall Response Rate (ORR) Per irRC

Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR). For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters.

Time frame: From start of treatment until end of treatment, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Progression-Free Survival (PFS) Per irRC

PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor evaluation. Tumor response was based on local investigator assessment per irRC. PFS was analyzed using Kaplan-Meier estimates.

Time frame: From start of treatment until first documented and confirmed progression or death due to any cause, assessed up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab

Overall Survival (OS)

OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. OS was estimated using Kaplan-Meier estimates.

Time frame: From start of treatment until death due to any cause, assessed up to 2 years for sabatolimab and 5.3 years for sabatolimab in combination with spartalizumab

Maximum Observed Serum Concentration (Cmax) of Sabatolimab

Pharmacokinetic (PK) parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.

Time frame: pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.

Time to Reach Maximum Serum Concentration (Tmax) of Sabatolimab

PK parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sabatolimab

PK parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Terminal Elimination Half-life (T1/2) of Sabatolimab

PK parameters were calculated based on sabatolimab serum concentrations by using non-compartmental methods. T1/2 was calculated by regression analysis of the terminal elimination phase. T1/2 was computed as 0.693/terminal elimination rate constant.

Time frame: pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the sabatolimab infusion on Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.

Maximum Observed Serum Concentration (Cmax) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.

Time frame: pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.

Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Terminal Elimination Half-life (T1/2) of Spartalizumab

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. T1/2 was calculated by regression analysis of the terminal elimination phase. T1/2 was computed as 0.693/terminal elimination rate constant.

Time frame: pre-infusion and 1, 24, 168, 240 and 336 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was 30 minutes. The duration of one cycle was 28 days.

Number of Participants With Anti-sabatolimab Antibodies

Immunogenicity was evaluated in serum in a validated three-tiered assay approach. Samples were screened for potential anti-sabatolimab antibodies and positive screen results were confirmed using a confirmatory assay. For confirmed anti-drug antibodies (ADA) positive samples, titers were determined. Patient ADA status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample * Treatment-boosted ADA-positive = ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample

Time frame: Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 1.9 years for sabatolimab and 4.9 years for sabatolimab in combination with spartalizumab)

Number of Participants With Anti-spartalizumab Antibodies

Immunogenicity was evaluated in serum in a validated three-tiered assay approach. Samples were screened for potential anti-spartalizumab antibodies and positive screen results were confirmed using a confirmatory assay. For confirmed anti-drug antibodies (ADA) positive samples, titers were determined. Patient ADA status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples * ADA-inconclusive post-baseline = patient who does not qualify as ADA-positive or ADA-negative * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample * Treatment-boosted ADA-positive = ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample

Time frame: Baseline (before first dose) and post-baseline (assessed throughout the treatment up to 4.9 years).

Baseline Expression of PD-L1

The tumor expression of programmed cell death-ligand 1 (PD-L1) was measured by immunohistochemical methods. This record summarizes the baseline expression of PD-1 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.

Time frame: Screening

Baseline Expression of CD8+

The tumor expression of CD8+ was measured by immunohistochemical methods. This record summarizes the baseline expression of CD8+ and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.

Time frame: Screening

Baseline Expression of TIM-3

The tumor expression of T-cell Immunoglobulin domain and Mucin domain-3 (TIM-3) was measured by immunohistochemical methods. This record summarizes the baseline expression of TIM-3 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.

Time frame: Screening

Baseline Expression of LAG-3

The tumor expression of lymphocyte-activation gene-3 (LAG-3) was measured by immunohistochemical methods. This record summarizes the baseline expression of LAG-3 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.

Time frame: Screening

Baseline Expression of CD163

The tumor expression of CD163 was measured by immunohistochemical methods. This record summarizes the baseline expression of CD163 and the clinical benefit of study treatment. Clinical benefit (BOR: CR, PR, SD or NCRNPD) and No clinical benefit (BOR: PD) was based on local investigator assessment per RECIST v1.1.

Time frame: Screening

Percentage Change From Baseline of Tumor Infiltrating Lymphocytes (TILs) Count

The count of TILs was performed by hematoxylin and eosin stain.

Time frame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 193 days)

Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period

Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.

Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 3 years

Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Sabatolimab

Number of participants with at least one dose reduction of sabatolimab and number of participants with at least one dose interruption of sabatolimab.

Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years

Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab

Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab.

Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years

Phase II: Dose Intensity of Sabatolimab

Dose intensity of sabatolimab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.

Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years

Phase II: Dose Intensity of Spartalizumab

Dose intensity of spartalizumab was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.

Time frame: From first dose of study medication up to last dose, with a maximum duration of 2.9 years