Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bristol Myers Squibb International Corporation

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Apr 2015 → 4 Feb 2025

Decision date (initial)

2024-04-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bristol-Myers Squibb International Corporation

External identifiers

EU CT number

2023-508067-70-00

EudraCT number

2014-002605-38

WHO UTN

U1111-1274-3895

ClinicalTrials.gov

NCT01968109

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Pharmacokinetic, Efficacy, Safety

Part A+B+A1:to assess safety,tolerability,DLTs,MTD of BMS986016 alone &in combo with nivo (advanced solid tumors); to gather preliminary efficacy information of BMS986016 alone
Part C:to further establish safety & tolerability of BMS986016 + nivo administered sequentially; to investigate the preliminary efficacy of BMS986016 in combo with nivo as measured by ORR, DCR,DOR (multiple tumor types)
Part D: to assess safety & tolerability of more convenient dosing regimen;Part D1-Q2W: to demonstrate preliminary clinical evidence of the treatment effect,measured by ORR,as determined by BICR using RECIST v1.1 (advanced melanoma);Part D1-Q4W: to confirm with Q4W dosing of BMS986016 160 mg in combo with nivo480 mg,the safety&efficacy of the Q2W dosing of BMS986016 80 mg in combo with nivo 240mg (advanced melanoma)
Part E: to demonstrate that 480 mg BMS986016 +480 mg nivo Q4W provides significantly greater clin benefit (increased ORR) vs 160mg BMS 986016+480 mg nivoQ4W dose (melanoma)

Secondary objectives 9

1. -To characterize PK of BMS986016 alone and with nivo
2. -To investigate preliminary ORR and/or DCR of BMS986016 alone and with nivo in subjects with advanced solid tumors(A,B,Dose Esc)
3. -To characterize immunogenicity of BMS986016 alone and with nivo
4. -To assess effect of BMS986016 alone & with nivo on QTc(A,B)
5. -To evaluate DOR, DCR, PFS rates at pre-specified time points based on BICR assessments using RECISTv1.1 in advanced melanoma subjects i)with, i)with a lack, i)regardless LAG-3 expression(D1, D2)
6. -To evaluate ORR, DCR, DOR, PFS rates at pre-specified time points based on Investigator assessments using RECISTv1.1 in advanced melanoma subjects i)with, i)with a lack, i)regardless LAG-3 expression(D1,D2)
7. -To assess the 1Y and 2Y landmark OS in advanced melanoma subjects(D1, D2)
8. -To assess safety and tolerability of more convenient dosing regimen in advanced melanoma subjects(D2)
9. -To evaluate clinical benefit of 480mg BMS986016 + 480mg nivo Q4W using DOR in melanoma subjects(E)

Conditions and MedDRA coding

Neoplasms by site

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. For Dose escalation: subjects with cervical, ovarian, bladder and CRC, head and neck, gastric and hepatocellular cancer naive to immunooncology agents; 1st line melanoma and 1st line/2nd line NSCLC; Renal Cell Carcinoma naive to IO; NSCLC progressing while on or after therapy with anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after treatment with anti-PD1 or anti-PDL1 with or without anti-CTLA-4.
2. For Dose Expansion: all of the above in escalation except for cervical, ovarian and CRC
3. Progressed, or been intolerant to, at least one standard treatment regimen, except for subjects in 1st line cohorts.
4. ECOG performance status of 0 to 2
5. At least 1 lesion with measurable disease at baseline
6. Availability of an existing tumor biopsy sample (and consent to allow pre-treatment tumor biopsy)

Exclusion criteria 4

1. Primary CNS tumors or solid tumors with CNS metastases as the only site of active disease
2. Autoimmune disease
3. Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
4. Uncontrolled CNS metastases

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 11

1. Proportion of subjects with Adverse Events (AEs)
2. Proportion of subjects with Serious Adverse Events (SAEs)
3. Proportion of Deaths
4. Proportion of subjects with laboratory abnormalities in blood
5. Proportion of subjects with laboratory abnormalities in blood serum
6. Proportion of subjects with laboratory abnormalities in urine
7. Objective response rate (ORR)
8. Disease control rate (DCR)
9. Duration of response (DOR)
10. Number of AEs in the Broad Scope MedDRA Anaphylactic Reaction SMQ
11. Proportion of subjects with AEs leading to discontinuation of treatment

Secondary endpoints 22

1. Maximum observed serum concentration (Cmax) of BMS-986016 administered both alone and in combination with nivolumab
2. Time of maximum observed serum concentration (Tmax) of BMS- 986016 administered both alone and in combination with nivolumab
3. Trough observed serum concentration (Ctrough) of BMS-986016 administered both alone and in combination with nivolumab
4. Concentration at the end of a dosing interval (Ctau) [Eg: concentration at 336 hours] of BMS-986016 administered both alone and in combination with nivolumab
5. Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-986016 administered both alone and in combination with nivolumab
6. Total body clearance (CLT) of BMS-986016 administered both alone and in combination with nivolumab
7. Volume of distribution at steady state (Vss) of BMS-986016 administered both alone and in combination with nivolumab
8. Effective elimination half-life that explains the degree of AUC accumulation observed (T-HALFeff AUC) of BMS- 986016 administered both alone and in combination with nivolumab
9. Effective elimination half-life that explains the degree of Cmax accumulation observed (T-HALFeff Cmax) of BMS-986016 administered both alone and in combination with nivolumab
10. Accumulation index; ratio of AUC(TAU) at steady state to AUC(TAU) after the first dose (AI_AUC) of BMS-986016 administered both alone and in combination with nivolumab
11. Cmax accumulation index; ratio of Cmax at steady state to Cmax after the first dose (AI_Cmax) of BMS-986016 administered both alone and in combination with nivolumab
12. Ctau accumulation index; ratio of Ctau at steady state to Ctau after the first dose (AI_Ctau) of BMS-986016 administered both alone and in combination with nivolumab
13. Degree of fluctuation (DF) or fluctuation index ([Cmax - Ctau]/Css,avg]) of BMS-986016 administered both alone and in combination with nivolumab
14. Immunogenicity measured by anti-drug antibody (ADA) for BMS- 986016 (all participants) and nivolumab
15. QTc interval from centrally read electrocardiograms (ECGs)
16. Best overall response (BOR)
17. Objective response rate (ORR)
18. Disease control rate (DCR)
19. Duration of response (DOR)
20. Progression-free survival (PFS) rates
21. Overall survival (OS)
22. Number of AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bristol Myers Squibb International Corporation

Sponsor organisation

Bristol Myers Squibb International Corporation

Address

Terhulpsesteenweg 185

City

Watermaal-Bosvoorde

Postcode

1170

Country

Belgium

Scientific contact point

Organisation

Bristol Myers Squibb International Corporation

Contact name

GSM-CT

Public contact point

Organisation

Bristol Myers Squibb International Corporation

Contact name

GSM-CT

Third parties 17

Locations

9 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 81 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications