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

NCT02608268 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CMBG453X21012015-002354-12
• Study Type: interventional
• Target: 252
• Locations: 9 countries
• Sites: 14

Brief Summary

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

Conditions

Advanced Malignancies

Keywords

Solid tumors; Melanoma; Non small cell lung cancer; NSCLC; Renal cell carcinoma; RCC; Phase I-Ib/II; MBG453; PDR001; Checkpoint inhibitor; PD-1; TIM-3

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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.

  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

• Phase Ib: 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.

  From first dose of study medication up to last dose, with a maximum duration of 4.9 years

• Phase I-Ib and Dose Ranging Part: Dose Intensity of Sabatolimab

  Dose intensity of sabatolimab Q2W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 14 days. Dose intensity of sabatolimab Q4W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.

  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

• Phase Ib: Dose Intensity of Spartalizumab

  Dose intensity of spartalizumab Q2W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 14 days. Dose intensity of spartalizumab Q4W was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.

  From first dose of study medication up to last dose, with a maximum duration of 4.9 years

• Phase II: Overall Response Rate (ORR) Per RECIST v1.1

  Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). 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 diameter of all target lesions, taking as reference the baseline sum of diameters.

  From start of treatment until end of treatment, assessed up to 2.9 years

Secondary Outcomes (27)

• Best Overall Response (BOR) Per RECIST v1.1

  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

  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

  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

  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

  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

Study Arms (10)

Phase I Dose escalation: MBG453 Q2W ROW

EXPERIMENTAL

Sabatolimab every 2 weeks (Q2W) in Phase I Dose Escalation Part in rest of the world (ROW) patients

Drug: MBG453

Phase I Dose escalation: MBG453 Q2W Japan

EXPERIMENTAL

Sabatolimab Q2W in Phase I Dose Escalation Part in Japanese patients

Drug: MBG453

Phase I Dose escalation: MBG453 Q4W ROW

EXPERIMENTAL

Sabatolimab every 4 weeks (Q4W) in Phase I Dose Escalation Part in ROW patients

Drug: MBG453

Phase I Dose escalation: MBG453 Q4W Japan

EXPERIMENTAL

Sabatolimab Q4W in Phase I Dose Escalation Part in Japanese patients

Drug: MBG453

Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W

EXPERIMENTAL

Sabatolimab Q2W in combination with spartalizumab Q2W in Phase Ib Dose Escalation Part

Drug: MBG453; Drug: PDR001

Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W

EXPERIMENTAL

Sabatolimab Q4W in combination with spartalizumab Q4W in Phase Ib Dose Escalation Part

Drug: MBG453; Drug: PDR001

Phase Ib Dose Escalation: MBG453 + Decitabine

EXPERIMENTAL

Sabatolimab in combination with decitabine in Phase Ib Dose Escalation Part. This arm was not opened for enrollment.

Drug: MBG453; Drug: Decitabine

Dose Ranging Part: MBG453 Q4W

EXPERIMENTAL

Sabatolimab Q4W in Dose Ranging Part

Drug: MBG453

Phase II: MBG453 + PDR001

EXPERIMENTAL

Sabatolimab Q4W in combination with spartalizumab Q4W in non-small cell lung carcinoma (NSCLC) and melanoma

Drug: MBG453; Drug: PDR001

Phase II: MBG453

EXPERIMENTAL

Sabatolimab alone in Phase II. This arm was not opened for enrollment.

Drug: MBG453

Interventions

MBG453 DRUG

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

Also known as: sabatolimab

Dose Ranging Part: MBG453 Q4W; Phase I Dose escalation: MBG453 Q2W Japan; Phase I Dose escalation: MBG453 Q2W ROW; Phase I Dose escalation: MBG453 Q4W Japan; Phase I Dose escalation: MBG453 Q4W ROW; Phase II: MBG453; Phase II: MBG453 + PDR001; Phase Ib Dose Escalation: MBG453 + Decitabine; Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W; Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W

PDR001 DRUG

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

Also known as: spartalizumab

Phase II: MBG453 + PDR001; Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W; Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W

Decitabine DRUG

commercially available chemotherapy

Phase Ib Dose Escalation: MBG453 + Decitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Sidney Kimmel CCC At JH Sidney Kimmel CCC

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute DFCI - Brookline

Boston, Massachusetts, 02215, United States

Location

UT M.D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Mays Cancer Ctr Uthsa Mdacc

San Antonio, Texas, 78229, United States

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2C1, Canada

Location

Novartis Investigative Site

Milan, MI, 20141, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Kashiwa, Chiba, 277 8577, Japan

Location

Novartis Investigative Site

Amsterdam, 1066 CX, Netherlands

Location

Novartis Investigative Site

Leiden, 2300 RC, Netherlands

Location

Novartis Investigative Site

Singapore, 168583, Singapore

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Geneva, CH 1211, Switzerland

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Related Publications (2)

• Lin CC, Curigliano G, Santoro A, Kim DW, Tai D, Hodi FS, Wilgenhof S, Doi T, Sabatos-Peyton C, Szpakowski S, Chitnis S, Xyrafas A, Gutzwiller S, Pastore A, Mach N. Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study. BMJ Open. 2024 Aug 29;14(8):e079132. doi: 10.1136/bmjopen-2023-079132.

  PMID: 39209782 DERIVED

• Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, Sarantopoulos J, Bedard PL, Lin CC, Hodi FS, Wilgenhof S, Santoro A, Sabatos-Peyton CA, Longmire TA, Xyrafas A, Sun H, Gutzwiller S, Manenti L, Naing A. Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3620-3629. doi: 10.1158/1078-0432.CCR-20-4746. Epub 2021 Apr 21.

  PMID: 33883177 DERIVED

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell

Interventions

sabatolimab; spartalizumab; Decitabine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2015
• First Posted: November 18, 2015
• Study Start: November 23, 2015
• Primary Completion: August 30, 2022
• Study Completion: August 30, 2022
• Last Updated: December 6, 2023
• Results First Posted: December 6, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share

Locations

IT (2); NL (2); SG (1); CH (1); US (4); JP (1); TW (1); KR (1); CA (1)