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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02608268

Collaborator

(none)

252

Enrollment

Locations

Arms

81.2

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignancies	Drug: MBG453 Drug: PDR001 Drug: Decitabine	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

252 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 23, 2015

Anticipated Primary Completion Date :

Aug 29, 2022

Anticipated Study Completion Date :

Aug 29, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose escalation MBG453 alone	Drug: MBG453 anti human TIM-3 monoclonal antibody
Experimental: Dose escalation MBG453 in combination with PDR001	Drug: MBG453 anti human TIM-3 monoclonal antibody Drug: PDR001 anti-human PD-1 monoclonal antibody
Experimental: Dose Ranging group	Drug: MBG453 anti human TIM-3 monoclonal antibody Drug: PDR001 anti-human PD-1 monoclonal antibody
Experimental: Dose Expansion of MBG453 alone	Drug: MBG453 anti human TIM-3 monoclonal antibody
Experimental: Dose Expansion of MBG453 in combination with PDR001	Drug: MBG453 anti human TIM-3 monoclonal antibody Drug: PDR001 anti-human PD-1 monoclonal antibody
Experimental: Safety run in for MBG453 in combination with decitabine	Drug: Decitabine commercially available chemotherapy

Outcome Measures

Primary Outcome Measures

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 [6.5 years]
Overall response rate (ORR) per RECIST v1.1 [6.5 years]
Incidence of Dose limiting toxicities (DLTs) during the first cycle of treatment with single agent MBG453 [5 years]
Incidence of DLTs during the first and second cycle of treatment with MBG453 in combination with PDR001 or in combination with decitabine [6.5 years]
Tolerability of MBG453 alone and in combination with PDR001 or in combination with decitabine, as assessed by number of dose changes [6.5 years]
Tolerability of MBG453 alone and in combination with PDR001 or in combination with decitabine, as assessed by number of dose interruptions [6.5 years]

Secondary Outcome Measures

Best Overall Response (BOR) per RECIST v1.1 [6.5 years]
Maximum observed serum concentration (Cmax) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Presence and concentration of anti-MBG453 antibodies [6.5 years]
Expression of Programmed Death Ligand-1 (PD-L1) markers [6.5 years]
Tumor Infiltrating Lymphocytes (TIL) counts [6.5 years]
Overall survival [6.5 years]
Duration of Response (DOR) per RECIST v1.1 [6.5 years]
Progressive Free Survival (PFS) per RECIST v1.1 [6.5 years]
Progressive Free Survival per Immune-related Response Criteria (irRC) [6.5 years]
Overall Response Rate (ORR) per irRC [6.5 years]
Overall Response Rate (ORR) per RECIST v1.1 [6.5 years]
Time of maximum observed serum concentration (Tmax) of MBG453 and PDR001 derived from serum concentration versus time [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 [6.5 years]
Area under the concentration-time in one dosing interval (AUCtau) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Area under the curve up to the last measurable concentration (AUClast) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Half-life (t1/2) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Clearance (CL) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Volume of distribution (V) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Accumulation ratio (AR) of MBG453 and PDR001 derived from serum concentration versus time [6.5 years]
Presence and concentration of anti-PDR001 antibodies [6.5 years]
Expression of immunological markers [6.5 years]
Expression of immune-related genes (RNA/protein) [6.5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Med Sidney Kimmel CCC	Baltimore	Maryland	United States	21231
2	Dana Farber Cancer Institute DFCI - Brookline	Boston	Massachusetts	United States	02215
3	UT M.D Anderson Cancer Center	Houston	Texas	United States	77030
4	Cancer Therapy and Research Center UT Health Science Center	San Antonio	Texas	United States	78229
5	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2C1
6	Novartis Investigative Site	Milano	MI	Italy	20141
7	Novartis Investigative Site	Rozzano	MI	Italy	20089
8	Novartis Investigative Site	Kashiwa	Chiba	Japan	277 8577
9	Novartis Investigative Site	Seoul		Korea, Republic of	03080
10	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
11	Novartis Investigative Site	Leiden		Netherlands	2300 RC
12	Novartis Investigative Site	Singapore		Singapore	169610
13	Novartis Investigative Site	Geneve 14		Switzerland	CH 1211
14	Novartis Investigative Site	Taipei		Taiwan	10002