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

Browse trials for

• Neoplasms 9,365

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

Neoplasms

9,365 studies on the registry are indexed under Neoplasms; 2,489 are open to participants now.

This study's enrollment of 252 is above the median of 50 across 7,253 interventional studies indexed under Neoplasms.

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Study arms

• Experimental
  Phase I Dose escalation: MBG453 Q2W ROW

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

  Drug: MBG453

• Experimental
  Phase I Dose escalation: MBG453 Q2W Japan

  Sabatolimab Q2W in Phase I Dose Escalation Part in Japanese patients

  Drug: MBG453

• Experimental
  Phase I Dose escalation: MBG453 Q4W ROW

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

  Drug: MBG453

• Experimental
  Phase I Dose escalation: MBG453 Q4W Japan

  Sabatolimab Q4W in Phase I Dose Escalation Part in Japanese patients

  Drug: MBG453

• Experimental
  Phase Ib Dose Escalation: MBG453 Q2W + PDR001 Q2W

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

  Drug: MBG453 · Drug: PDR001

• Experimental
  Phase Ib Dose Escalation: MBG453 Q4W + PDR001 Q4W

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

  Drug: MBG453 · Drug: PDR001

• Experimental
  Phase Ib Dose Escalation: MBG453 + Decitabine

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

  Drug: MBG453 · Drug: Decitabine

• Experimental
  Dose Ranging Part: MBG453 Q4W

  Sabatolimab Q4W in Dose Ranging Part

  Drug: MBG453

• Experimental
  Phase II: MBG453 + PDR001

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

  Drug: MBG453 · Drug: PDR001

• Experimental
  Phase II: MBG453

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

  Drug: MBG453

Interventions

• DrugMBG453

  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

• DrugPDR001

  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

• DrugDecitabine

  commercially available chemotherapy

Primary outcomes

1. 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

2. 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)

3. 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

4. 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.

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

5. 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.

   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

6. 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.

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

7. 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.

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

Secondary outcomes

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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.

8. 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.

   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.

9. 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.

   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.

10. 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.

11. 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.

12. 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.

    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.

13. 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.

    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.

14. 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.

15. 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)

16. 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).

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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)

23. 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

24. 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

25. 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

26. 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

27. 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

Baseline characteristics

Publications

• 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. Erratum In: Clin Cancer Res. 2024 Sep 3;30(17):3957. doi: 10.1158/1078-0432.CCR-24-2131. PubMed 33883177 ↗

Study documents

• Study protocol · Aug 31, 2020
• Statistical analysis plan · Sep 29, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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