Detailed Description:
Study Design :
This open label (all participants know the identity of the study drug), multicenter (more
than one study site), first-in-human study consisting of 2 parts. Part 1 is a dose escalation
and Part 2 is a dose expansion cohort. Part 1 has been completed.
Part 2 new patient populations examined:
- Group F: Patients with NSCLC with documented NRG1 fusion
- Group G: Patients with pancreatic adenocarcinoma with documented NRG1 fusion
- Group H: Patients with any other solid tumor with documented NRG1 fusion
For these new patient populations, Part 2 will further characterize the safety and
tolerability of the selected dose level of zenocutuzumab (MCLA-128), as well as assessment of
CBR, defined as the proportion of patients with a CR, PR or durable SD (SD for at least 24
weeks in duration). For the new patient populations, overall response rate (ORR) and duration
of response (DOR) will be described.
The study consists of 3 periods: Screening period (up to 28 days prior to the first dose of
study drug); Treatment period (treatment cycles of 28 days); and Follow Up period (through 30
days after the last dose and quarterly checks for survival data for up to 2 years).
Participants' safety will be monitored throughout the study.
Inclusion Criteria:
- At least one measurable lesion according to RECIST v1.1 OR evaluable disease for a
limited number of patients (up to 15) in Group H;
- Performance status of ECOG 0 - 2;
- Estimated life expectancy of at least 12 weeks;
- Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1;
- Treatment with anti-cancer medication or investigational drugs within the following
intervals before the first dose of MCLA-128:
1. >14 days or >5 half-lives prior to study entry, whichever is shorter.
2. >14 days for radiotherapy.
- Recovery from major surgery or other complication to ≤ Grade 2 or baseline ;
- Absolute neutrophil count ≥1.5 x 109/L without colony stimulating factor support for
at least 7 days prior to screening;
- Platelets ≥75 x 109/L without transfusion support for at least 7 days prior to
screening;
- Hemoglobin ≥8 g/dL or ≥5 mmol/L;
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of
normal (ULN) and total bilirubin ≤1.5 x ULN; in cases of metastatic liver involvement,
ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed; in cases of antecedents
of Gilbert's syndrome when total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN
will be allowed;
- Estimated glomerular filtration rate (GFR) of >30 mL/min
- Able to provide a tumor biopsy sample (fresh strongly preferred or else archival);
- Not pregnant or nursing
- Fertile patients must use effective contraception during and for 6 month after
completion of study therapy;
- Patients must have received prior standard therapy appropriate for their tumor type
and stage of disease, or in the opinion of the Investigator, would be unlikely to
tolerate or derive clinically meaningful benefit from appropriate standard of care
therapy or no satisfactory alternative treatment options are available;
- Locally-advanced unresectable or metastatic solid tumor malignancy with documented
NRG1 gene fusion, identified through molecular assays such as next generation
sequencing-based assays [DNA or RNA], as routinely performed at CLIA or other
similarly-certified laboratories.
Exclusion Criteria:
- Pregnant or lactating;
- Presence of an active uncontrolled infection or an unexplained fever;
- Known hypersensitivity to any of the components of MCLA-128;
- Known HIV, active Hepatitis B without receiving antiviral treatment, or Hepatitis C;
patients treated for Hepatitis C and have undetectable viral loads are eligible
- Known symptomatic or unstable brain metastases;
- Patients with leptomeningeal metastases;
- Presence of LVEF <50% on the screening echocardiogram; or history or presence of any
significant cardiovascular disease, including unstable angina or myocardial infarction
within 12 months prior to screening, congestive heart failure (NYHA Class III or IV),
or ventricular arrhythmia requiring medication;
- Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or
carcinoma in situ of the uterine cervix) unless the tumor was treated with curative
intent more than 2 years prior to study entry;
- Presence of any other medical or psychological condition deemed by the Investigator to
be likely to interfere with a patient's ability to sign informed consent, cooperate or
participate in the study, or interfere with the interpretation of the results.
Primary outcome:
1. Objective overall response rate (ORR) as per local investigator's assessment (Time Frame - 36 months):
Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
2. Duration of response per RECIST v1.1 as per local Investigator's assessment. (Time Frame - 36 Months):
To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally
Secondary outcome:
1. Overall response rate as per central review (Time Frame - 36 months):
Assess the anti-tumor response of zenocutuzumab (MCLA-128) by RECIST v1.1 as assessed centrally
2. Clinical Benefit Rate (CBR) of zenocutuzumab (MCLA-128) assessed locally and centrally (Time Frame - 36 months):
CBR assessed as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 24 weeks) by RECIST v1.1 .
3. Duration of Response as per central review (Time Frame - 36 months):
To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed centrally
4. Time to response per RECIST v1.1. as per local Investigator's assessment. (Time Frame - 36 months):
To assess time to onset of response in patients with NRG1 fusions as assessed locally
5. Time to response per RECIST v1.1. as per central review (Time Frame - 36 months):
To assess time to onset of response in patients with NRG1 fusions as assessed centrally
6. Characterize the safety and tolerability of zenocutuzumab (MCLA-128) (Time Frame - 6-12 months):
Number of participants with Adverse Events (AE) and Serious Adverse Events (SAE)
7. Maximum plasma concentration [Cmax] (Time Frame - 36 months):
Assess the Cmax of zenocutuzumab (MCLA-128)
8. Volume of distribution [V] (Time Frame - 36 months):
Assess the volume of distribution of zenocutuzumab (MCLA-128)
9. Volume of distribution at steady state [Vss] (Time Frame - 36 months):
Assess the volume of distribution of zenocutuzumab (MCLA-128) at steady state
10. Area under the concentration versus time curve from time zero to time t [AUC0-t] (Time Frame - 36 months):
Assess the Area under the concentration versus time curve from time zero to time t [AUC0-t] of zenocutuzumab (MCLA-128)
11. half-life [t1/2] (Time Frame - 36 months):
Assess the half-life of zenocutuzumab (MCLA-128)
12. area under the concentration versus time curve [AUC0-∞] (Time Frame - 36 months):
Assess the area under the concentration versus time curve [AUC0-∞] of zenocutuzumab (MCLA-128)
13. time to reach maximum concentration [tmax] (Time Frame - 36 months):
Assess the time to reach maximum concentration [tmax] of zenocutuzumab (MCLA-128)
14. Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128) (Time Frame - 36 months):
Assess the Incidence of anti-drug antibodies against zenocutuzumab (MCLA-128)
15. serum titers of anti-drug antibodies (Time Frame - 36 months):
Assess serum titers of anti-drug antibodies
16. Evaluation of progression free survival (PFS) (Time Frame - 36 months)
17. Evaluation of overall survival (OS) (Time Frame - 12 months)
- Experimental: Part 2 Pancreatic adenocarcinoma harboring NRG1 fusion
Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks. - Experimental: Part 2 NSCLC cancer harboring NRG1 fusion
Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks. - Experimental: Part 2 Solid tumour (basket) harboring NRG1 fusion
Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks.
- zenocutuzumab (MCLA-128) (bispecific / MCLA-128 / ):
full length IgG1 bispecific antibody targeting HER2 and HER3
Quelle: ClinicalTrials.gov
