daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04952753

Collaborator

(none)

266

Enrollment

Locations

Arms

39.1

Anticipated Duration (Months)

11.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the preliminary efficacy and safety of NIS793 and other novel investigational combinations with standard of care (SOC) anti-cancer therapy vs SOC anti-cancer therapy for the second line treatment of mCRC.

This study aims to explore whether different mechanisms of action may reverse resistance and improve responsiveness to the currently considered SOC anti-cancer therapy in the second line metastatic colorectal cancer (mCRC) setting.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: NIS793 Drug: Bevacizumab Drug: Modified FOLFOX6 Drug: FOLFIRI Drug: Tislelizumab	Phase 2

Detailed Description

This is an open-label, multi-center, phase II, 2-part platform study with Safety run-in and Expansion parts.

The platform design of this study is adaptive to allow flexibility in the introduction of additional treatment arms with new investigational drugs in combination with SOC anti-cancer therapy for the second line treatment of mCRC.

The study will include a control arm that will enroll participants treated with SOC anti-cancer therapy (bevacizumab with mFOLFOX6 or FOLFIRI) for the second line treatment of mCRC. The choice of the chemotherapy medications (mFOLFOX6 or FOLFIRI) will be determined by the Investigator based on prior exposure to oxaliplatin or irinotecan.

Each investigational arm will include a combination of an investigational drug and the SOC anti-cancer therapy. The first investigational arm of the study will explore the combination of anti-transforming growth factor β (TGF-β) monoclonal antibody, NIS793 with SOC anti-cancer therapy. The second investigational arm of the study will explore the combination of anti-transforming growth factor β (TGF-β) monoclonal antibody, NIS793 with Tislelizumab, which is an anti-PD1 monoclonal antibody, and SOC anti-cancer therapy. Combination of other investigational drugs with SOC anti-cancer therapy may be added by protocol amendments an additional investigational arms.

In each investigational arm, a Safety run-in part will be conducted before opening the expansion part to confirm the recommended phase 2 dose (RP2D) for a combination of any investigational drug with SOC anti-cancer therapy unless the dose has been confirmed externally to this trial.

The decision to open the Expansion part of the study will be based on dose confirmation of investigational drug with available safety, relevant PK and other relevant data from Safety run-in part. Participants in the expansion part will be randomized in 1:2 ratio to the control arm or investigational arm.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

266 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Multi-center, ph II Platform Study Evaluating the Efficacy and Safety of NIS793 and Other New Investigational Drug Combinations With SOC Anti-cancer Therapy for the 2L Treatment of Metastatic Colorectal Cancer (mCRC)

Actual Study Start Date :

Nov 15, 2021

Anticipated Primary Completion Date :

Jan 30, 2025

Anticipated Study Completion Date :

Feb 17, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Safety run-in: NIS793+SOC (Investigational arm 1) In the safety run-in part for investigational arm 1, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 to confirm the RP2D of the NIS793	Drug: NIS793 Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part. Drug: Bevacizumab Bevacizumab will be administered IV Drug: Modified FOLFOX6 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV] Other Names: 5FU+Leucovorin+Oxaliplatin Drug: FOLFIRI 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV] Other Names: 5FU+Leucovorin+Irinotecan
Experimental: Expansion: NIS793+SOC (Investigational arm 1) In the expansion part, participants in the investigational arm 1 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI) and NIS793 at the RP2D defined in the safety run-in	Drug: NIS793 Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part. Drug: Bevacizumab Bevacizumab will be administered IV Drug: Modified FOLFOX6 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV] Other Names: 5FU+Leucovorin+Oxaliplatin Drug: FOLFIRI 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV] Other Names: 5FU+Leucovorin+Irinotecan
Active Comparator: Expansion: SOC (control arm) In the expansion part, participants in the control arm will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI)	Drug: Bevacizumab Bevacizumab will be administered IV Drug: Modified FOLFOX6 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV] Other Names: 5FU+Leucovorin+Oxaliplatin Drug: FOLFIRI 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV] Other Names: 5FU+Leucovorin+Irinotecan
Experimental: Safety run-in: NIS793+Tislelizumab+SOC (Investigational arm 2) In the safety run-in part for investigational arm 2, participants will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FOLFOX6 or FOLFIRI), NIS793 and tislelizumab to confirm the RP2D of NIS793.	Drug: NIS793 Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part. Drug: Bevacizumab Bevacizumab will be administered IV Drug: Modified FOLFOX6 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV] Other Names: 5FU+Leucovorin+Oxaliplatin Drug: FOLFIRI 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV] Other Names: 5FU+Leucovorin+Irinotecan Drug: Tislelizumab Investigational drug tislelizumab will be administered intravenously (IV). Other Names: VDT482
Experimental: Expansion: NIS793+Tislelizumab+SOC (Investigational arm 2) In the expansion part, participants in the investigational arm 2 will be treated with a combination of SOC anti-cancer therapy (bevacizumab with either modified FLOFOX6 or FOLFIRI) with NIS793 and tislelizumab at the RP2D for NIS793 defined in the safety run-in	Drug: NIS793 Investigational drug NIS793 will be administered intravenously (IV) at the dose and schedule determined in the safety run-in part. Drug: Bevacizumab Bevacizumab will be administered IV Drug: Modified FOLFOX6 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and oxaliplatin [administered IV] Other Names: 5FU+Leucovorin+Oxaliplatin Drug: FOLFIRI 5-fluorouracil [continuous infusion], leucovorin [administered IV] (or levoleucovorin [administered IV]), and irinotecan [administered IV] Other Names: 5FU+Leucovorin+Irinotecan Drug: Tislelizumab Investigational drug tislelizumab will be administered intravenously (IV). Other Names: VDT482

Outcome Measures

Primary Outcome Measures

Safety run-in: Percentage of participants with dose limiting toxicities (DLTs) during the first cycle (4 weeks) of treatment. [Up to 4 weeks]
Percentage of participants with DLTs during the first cycle of treatment. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness or concomitant medication that occurs within the first cycle of treatment with NIS793 with or without tislelizumab in combination with Bevacizumab and modified FOLFOX6/ FOLFIRI and meets protocol defined DLT criteria.
Expansion: Progression-free survival (PFS) by investigator assessment per RECIST 1.1 [From randomization up to disease progression or death, assessed up to approximately 12 months]
PFS defined as the time from the date of enrollment (run-in part) or randomization (randomized part) to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause.

Secondary Outcome Measures

Safety run-in: Percentage of participants with Adverse Events (AEs) [Up to approximately 12 months]
Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments
Safety run-in: Percentage of participants with dose interruptions and dose reductions of investigational drug [Upto approximately 12 months]
Tolerability measured by the percentage of subjects who have dose adjustments (interruptions or reductions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)
Safety run-in: Dose intensity of investigational drug [Up to approximately 12 months]
Tolerability measured by the dose intensity of investigational drug (e.g. NIS793, NIS793+tislelizumab). Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
Safety run-in: PFS by investigator assessment per RECIST 1.1 [From enrollment up to disease progression or death, assessed up to approximately 12 months]
PFS defined as the time from the date of enrollment to the date of the first documented progression based on investigator assessment and according to RECIST 1.1 or death due to any cause.
Safety run-in: Overall response rate (ORR) by investigator assessment per RECIST 1.1 [Up to approximately 12 months]
ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
Safety run-in: Disease control rate (DCR) by investigator assessment per RECIST 1.1 [Up to approximately 12 months]
DCR is the proportion of participants with BOR of CR or PR or stable disease (SD) as per investigator assessment and according to RECIST 1.1
Safety run-in: Duration of response (DOR) by investigator assessment per RECIST 1.1 [From first documented response up to disease progression or death, assessed up to approximately 12 months]
DOR is defined as the duration of time between the date of the first documented response (CR or PR) and the date of first documented progression or death due to any cause
Safety run-in part: Overall Survival (OS) [From enrollment up to death, assessed up to approximately 12 months]
OS is defined as the time from the date of enrollment to date of death due to any cause.
Safety run-in: Time to response (TTR) by investigator assessment per RECIST 1.1 [From enrollment up to first documented response, assessed up to approximately 12 months]
TTR is defined as the duration of time between the date of enrollment and the date of first documented response of either CR or PR.
Expansion: Percentage of participants with Adverse Events (AEs) [Up to approximately 12 months]
Percentage of participants with AEs and SAEs including changes in laboratory parameters, vital signs, body weight and cardiac assessments
Expansion part: Percentage of participants with dose interruptions and dose reductions of investigational drug [Up to approximately 12 months]
Tolerability measured by the percentage of subjects who have dose adjustments (interruptions) of investigational drug (e.g. NIS793, NIS793+tislelizumab)
Expansion: Dose intensity of investigational drug [Up to approximately 12 months]
Tolerability measured by the dose intensity of investigational drug (e.g. NIS793, NIS793+Tislelizumab). Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
Expansion: Overall response rate (ORR) by investigator assessment per RECIST 1.1 [Up to approximately 12 months]
ORR is defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per investigator assessment and according to RECIST 1.1
Expansion: Disease control rate (DCR) by investigator assessment per RECIST 1.1 [Up to approximately 12 months]
DCR is the proportion of participants with BOR of CR or PR or stable disease (SD) as per investigator assessment and according to RECIST 1.1
Expansion part: Overall Survival (OS) [From randomization up to death, assessed up to approximately 12 months]
OS is defined as the time from the date of enrollment to date of death due to any cause.
Expansion: Time to response (TTR) by investigator assessment per RECIST 1.1 [From enrollment up to first documented response, assessed up to approximately 12 months]
TTR is defined as the duration of time between the date of enrollment and the date of first documented response of either CR or PR.
Maximum concentration (Cmax) of NIS793 [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Cmax of NIS793
Maximum concentration (Cmax) of tislelizumab [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Cmax of tislelizumab
Maximum concentration (Cmax) of bevacizumab [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Cmax of bevacizumab
Maximum concentration (Cmax) of irinotecan and its metabolite (SN38) [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Cmax of irinotecan and SN-38
Trough Concentration (Ctrough) of NIS793 [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Ctrough of NIS793
Trough Concentration (Ctrough) tislelizumab [From the date of first study drug intake up to approximately 12 months]
Blood samples will be collected at indicated time-points for analysis of Ctrough of tislelizumab
Trough Concentration (Ctrough) of bevacizumab [From the date of first study intake up to approximately 12 months.]
Blood samples will be collected at indicated time-points for analysis of Ctrough of bevacizumab
Trough Concentration (Ctrough) of irinotecan and its metabolite (SN38) [From the date of first study drug intake up to approximately 12 months.]
Blood samples will be collected at indicated time-points for analysis of Ctrough of irinotecan and SN-38
Antidrug antibodies (ADA) at baseline [Baseline]
Prevalence of ADA (anti-NIS793, anti-bevacizumab, anti-tislelizumab) at baseline is defined as the proportion of participants who have an ADA positive result at baseline
ADA incidence on treatment [From the date of first study drug intake up to approximately 12 months]
Incidence of ADA (anti-NIS793, anti-bevacizumab, anti-tislelizumab) on treatment is defined as the proportion of participants who are treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Participants age 18 or older with histologically or cytologically confirmed (by local laboratory and local clinical guidelines) metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery in the opinion of the investigator and progressed on or within 6 months after the last dose of one prior line of systemic anti-cancer therapy administered for metastatic disease.
Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
Adequate organ function (assessed by central laboratory for eligibility).

Key Exclusion Criteria:

Previously administered TGF-β targeted therapies or anti-cancer immunotherapy.
Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAFV600 mutation positive colorectal cancer.
Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory).
For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory).
Participants who have not recovered from a major surgery performed prior to start of study treatment or have had a major surgery within 4 weeks prior to start of study treatment.
Impaired cardiac function or clinically significant cardio-vascular disease.
Participants with conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.
Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment.
Pregnant or breast-feeding women.
Women of childbearing potential, unless willing to use highly effective contraception methods during treatment and after stopping study treatments as required.

Other inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Astera Cancer Center	East Brunswick	New Jersey	United States	08816
2	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
3	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
4	Novartis Investigative Site	Perth	Western Australia	Australia
5	Novartis Investigative Site	Brno	Czech Republic	Czechia	656 53
6	Novartis Investigative Site	Hradec Kralove	CZE	Czechia	500 05
7	Novartis Investigative Site	Avignon Cedex		France	84082
8	Novartis Investigative Site	Creteil		France	94010
9	Novartis Investigative Site	Reims		France	51092
10	Novartis Investigative Site	Essen		Germany	45147
11	Novartis Investigative Site	Frankfurt		Germany	60488
12	Novartis Investigative Site	Hamburg		Germany	20249
13	Novartis Investigative Site	Haifa		Israel	3109601
14	Novartis Investigative Site	Petach Tikva		Israel	4941492
15	Novartis Investigative Site	Nagoya	Aichi	Japan	464 8681
16	Novartis Investigative Site	Seoul		Korea, Republic of	05505
17	Novartis Investigative Site	Singapore		Singapore	119074
18	Novartis Investigative Site	Sabadell	Barcelona	Spain	08208
19	Novartis Investigative Site	Santander	Cantabria	Spain	39008
20	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
21	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
22	Novartis Investigative Site	Madrid		Spain	28040
23	Novartis Investigative Site	Tainan		Taiwan	70403
24	Novartis Investigative Site	Taipei		Taiwan	10002