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

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ClinicalTrials.gov Identifier: NCT02608268
Recruitment Status : Recruiting
First Posted : November 18, 2015
Last Update Posted : February 10, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 15, 2015
First Posted Date  ICMJE November 18, 2015
Last Update Posted Date February 10, 2020
Actual Study Start Date  ICMJE November 23, 2015
Estimated Primary Completion Date October 14, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2020)
  • Safety and tolerability of MBG453 alone and in combination with PDR001 or in combination with decitabine as assessed by incidence and severity of adverse events [ Time Frame: 6.5 years ]
  • Overall response rate (ORR) per RECIST v1.1 [ Time Frame: 6.5 years ]
  • Incidence of Dose limiting toxicities (DLTs) during the first cycle of treatment with single agent MBG453 [ Time Frame: 5 years ]
  • Incidence of DLTs during the first and second cycle of treatment with MBG453 in combination with PDR001 or in combination with decitabine [ Time Frame: 6.5 years ]
  • Tolerability of MBG453 alone and in combination with PDR001 or in combination with decitabine, as assessed by number of dose changes [ Time Frame: 6.5 years ]
  • Tolerability of MBG453 alone and in combination with PDR001 or in combination with decitabine, as assessed by number of dose interruptions [ Time Frame: 6.5 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 17, 2015)
  • Safety and tolerability of MBG453 alone and in combination with PDR001 as assessed by incidence and severity of adverse events [ Time Frame: Up to 90 days after post study treatment ]
  • Overall response rate (ORR) per RECIST v1.1 [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Incidence of Dose limiting toxicities (DLTs) during the first cycle of treatment with single agent MBG453 [ Time Frame: During Cycle 1 (28 days) ]
  • Incidence of DLTs during the first and second cycle of treatment with MBG453 in combination with PDR001 [ Time Frame: During Cycle 1 and Cycle 2 ( total of 56 days) ]
  • Tolerability of MBG453 alone and in combination with PDR001 as assessed by number of dose changes or interruptions [ Time Frame: Up to 90 days after post study treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2020)
  • Best Overall Response (BOR) per RECIST v1.1 [ Time Frame: 6.5 years ]
  • Maximum observed serum concentration (Cmax) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Presence and concentration of anti-MBG453 antibodies [ Time Frame: 6.5 years ]
  • Expression of Programmed Death Ligand-1 (PD-L1) markers [ Time Frame: 6.5 years ]
  • Tumor Infiltrating Lymphocytes (TIL) counts [ Time Frame: 6.5 years ]
  • Overall survival [ Time Frame: 6.5 years ]
  • Duration of Response (DOR) per RECIST v1.1 [ Time Frame: 6.5 years ]
  • Progressive Free Survival (PFS) per RECIST v1.1 [ Time Frame: 6.5 years ]
  • Progressive Free Survival per Immune-related Response Criteria (irRC) [ Time Frame: 6.5 years ]
  • Overall Response Rate (ORR) per irRC [ Time Frame: 6.5 years ]
  • Overall Response Rate (ORR) per RECIST v1.1 [ Time Frame: 6.5 years ]
  • Time of maximum observed serum concentration (Tmax) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Area under the concentration-time in one dosing interval (AUCtau) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Area under the curve up to the last measurable concentration (AUClast) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Half-life (t1/2) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Clearance (CL) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Volume of distribution (V) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Accumulation ratio (AR) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 6.5 years ]
  • Presence and concentration of anti-PDR001 antibodies [ Time Frame: 6.5 years ]
  • Expression of immunological markers [ Time Frame: 6.5 years ]
  • Expression of immune-related genes (RNA/protein) [ Time Frame: 6.5 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2015)
  • Best Overall Response (BOR) per RECIST v1.1 [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Maximum observed serum concentration (Cmax) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Presence and concentration of anti-MBG453 antibodies [ Time Frame: On Day 1 of Cycle, 1, 2, 3, 4, 5 and 6 on Day 1 and End of treatment.An average of 2 years duration is expected. ]
  • Expression of Programmed Death Ligand-1 (PD-L1) markers [ Time Frame: Screening (Day -28 to -1), after Cycle 3 (Day 84) and at the end of the study.An average of 2 years duration is expected. ]
  • Tumor Infiltrating Lymphocytes (TIL) counts [ Time Frame: Screening (Day -28 to -1), after Cycle 3 (Day 84) and at the end of the study.An average of 2 years duration is expected. ]
  • Overall survival [ Time Frame: From time of start treatment until the date of death.An average of 1 year duration is expected. ]
  • Duration of Response (DOR) per RECIST v1.1 [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Progressive Free Survival (PFS) per RECIST v1.1 [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Progressive Free Survival per Immune-related Response Criteria (irRC) [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Overall Response Rate (ORR) per irRC [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Overall Response Rate (ORR) per RECIST v1.1 [ Time Frame: Every 8 weeks until week 40, and then every 12 weeks until end of disease progression follow-up. An average of 1 year duration is expected. ]
  • Time of maximum observed serum concentration (Tmax) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Area under the concentration-time in one dosing interval (AUCtau) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Area under the curve up to the last measurable concentration (AUClast) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Half-life (t1/2) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Clearance (CL) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Volume of distribution (V) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Accumulation ratio (AR) of MBG453 and PDR001 derived from serum concentration versus time [ Time Frame: 19 timepoints up to an average of 1 year duration expected. ]
  • Presence and concentration of anti-PDR001 antibodies [ Time Frame: On Day 1 of Cycle, 1, 2, 3, 4, 5 and 6 on Day 1 and End of treatment.An average of 2 years duration is expected. ]
  • Expression of immunological markers [ Time Frame: Screening (Day -28 to -1), after Cycle 3 (Day 84) and at the end of the study.An average of 2 years duration is expected. ]
  • Expression of immune-related genes (RNA/protein) [ Time Frame: Screening (Day -28 to -1), after Cycle 3 (Day 84) and at the end of the study.An average of 2 years duration is expected. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies
Official Title  ICMJE Phase I-Ib/II Open-label Multi-center Study of the Safety and Efficacy of MBG453 as Single Agent and in Combination With PDR001 in Adult Patients With Advanced Malignancies
Brief Summary The purpose of this first-in-human study of MBG453 is 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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Malignancies
Intervention  ICMJE
  • Drug: MBG453
    anti human TIM-3 monoclonal antibody
  • Drug: PDR001
    anti-human PD-1 monoclonal antibody
  • Drug: Decitabine
    commercially available chemotherapy
Study Arms  ICMJE
  • Experimental: Dose escalation MBG453 alone
    Intervention: Drug: MBG453
  • Experimental: Dose escalation MBG453 in combination with PDR001
    Interventions:
    • Drug: MBG453
    • Drug: PDR001
  • Experimental: Dose Ranging group
    Interventions:
    • Drug: MBG453
    • Drug: PDR001
  • Experimental: Dose Expansion of MBG453 alone
    Intervention: Drug: MBG453
  • Experimental: Dose Expansion of MBG453 in combination with PDR001
    Interventions:
    • Drug: MBG453
    • Drug: PDR001
  • Experimental: Safety run in for MBG453 in combination with decitabine
    Intervention: Drug: Decitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 7, 2020)
269
Original Estimated Enrollment  ICMJE
 (submitted: November 17, 2015)
250
Estimated Study Completion Date  ICMJE October 15, 2021
Estimated Primary Completion Date October 14, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Other inclusion/exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Canada,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Singapore,   Switzerland,   Taiwan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02608268
Other Study ID Numbers  ICMJE CMBG453X2101
2015-002354-12 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP