A study of the investigational drug MCLA-128 which is an antibody that is specific to both HER2 and HER3 receptors that are associated with solid tumors

• Register: EUCTR
• Last refreshed on: 3 October 2023
• Main ID: EUCTR2014-003277-42-NL
• Date of registration: 01/12/2014
• Prospective Registration: Yes
• Primary sponsor: Merus N.V.
• Public title: A study of the investigational drug MCLA-128 which is an antibody that is specific to both HER2 and HER3 receptors that are associated with solid tumors
• Scientific title: A Phase I/II Study of MCLA-128, a full length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors (eNRGy)
• Date of first enrolment: 09/03/2015
• Target sample size: 458
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003277-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: Double blind: Parallel group: Cross over: Other: yes Other trial design description: Part 2 is parallel design, Part 1 is not If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Canada, Denmark, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, Norway, Portugal, Singapore, Spain, Sweden, Taiwan, United Kingdom, United States

Contacts

• Name: MCLA-128-CL01 Project Physician
• Affiliation: Merus N.V

• Name: MCLA-128-CL01 Project Physician
• Affiliation: Merus N.V

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age =18 yrs
2. =1 measurable lesion, RECIST v1.1 or evaluable disease for a limited
number of patients in group H
3. ECOG 0, 1 or 2
4. life expectancy =12 wks
5. Toxicities incurred as a result of previous anti-cancer therapy resolved to =Grade 1 except for alopecia, Grade 2 sensory neurotoxicity, or any other toxicity that in the opinion of the investigator does not affect the assessment of adverse events related to the study drug
6. Treatment with anti-cancer or investigational product within set intervals before first dose of IMP:
a. >14d or >5 half-lives prior to study entry, whichever is shorter.
b. >14d for radiotherapy. Note: A less than 1-week wash-out period is permitted only for palliative radiation to non-CNS disease with Sponsor approval.
7. Recovery from prior surgery/other procedure/ complication to = Grade 2 or to baseline condition that in opinion of the investigator does not affect the assessment of adverse events related to the study drug;
8. Screening Lab values:
a. Absolute neutrophil count =1.5 x 109/L without colony stimulating factor support for at least 7 days prior to Screening;
b. Platelets =75 x 10^9/L without transfusion support for at least 7 days prior to Screening;
c. Hemoglobin =8 g/dL or =5 mmol/L;
d. ALT, AST =3 x ULN and total bilirubin =1.5 x ULN (for exceptions please refer to protocol)
e. Estimated glomerular filtration rate (GFR) of >30 mL/min based on the Cockroft-Gault formula;
9. Able to provide at baseline a mandatory tumor biopsy sample, preferably a block. If safe/feasible, a fresh FFPE biopsy sample is preferred; archival tissue is acceptable (preferably not more than 2 years old
Note 1: For patients who received afatinib or other HER-targeting agents, a biopsy collected after the last line of treatment is strongly preferred to assess for mechanisms of acquired resistance
Note 2: For patients with a locally confirmed NRG1 gene fusion, when archival tissue is not available and collection of a fresh biopsy is not safe or feasible during the screening period, these patients will be allowed to enroll in the MCLA128-CL01 trial provided they meet all other inclusion/exclusion criteria.
10. Negative pregnancy test at Screening and =7 days of D1
Note: Women with amenorrhea associated with prior treatment with antineoplastic medications are still considered as being of child-bearing potential.
11. Sexually active male and female patients of childbearing potential must agree to use one of the highly effective methods of birth control during entire
study and 6 months after final administration of MCLA-128
12. Give written informed consent
13. Capable of understanding protocol requirements, is willing and able to comply with study procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or
blood) and long-term sample storage, additional consent is required
14. 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;
15. Histologic or cytologic diagnosis of locally-advanced unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified through molecular assays such as PCR, next generation sequencing-based assays [DNA or RNA], as routinely performed at CLIA or o
Exclusion criteria:
1. Pregnant or lactating;
2. Presence of an active uncontrolled infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever or a clinically insignificant minor infection may be enrolled (i.e. mild upper respiratory infection);
3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies;
4. Patients with the following infectious diseases are excluded:
a. known HIV
b. active Hepatitis B infection (HBsAg positive) without receiving antiviral treatment
Note:
• Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least = 7 days before the initiation of the study treatment.
• Patients with antecedents of Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible.
c. positive test for Hepatitis C ribonucleic acid (HCV RNA)
Note:
• Patients in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a
sustained response after antiviral treatment and show absence of detectable HCV RNA = 6 months (with the use of IFN-free regimens) or = 12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible;
NOTE: Patients without known or suspected HIV, Hepatitis B or Hepatitis C infection do not require specific viral testing during the screening period.
5. Known symptomatic or unstable brain metastases. Patients with asymptomatic brain metastases are eligible to participate if the metastases have been radiographically and clinically stable for at least
one month. If on steroids for this indication, the patient must be on a stable dose for at least one month.
6. Patients with leptomeningeal metastases
7. 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 or palliative intent and in the opinion of the investigator, with sponsor agreement, the previous or concurrent malignancy condition doesn't affect the assessment of safety and efficacy of the study drug;
8. 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;
9. 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Solid Tumors
MedDRA version: 21.0 Level: LLT Classification code 10049280 Term: Solid tumour System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Not available
Product Code: MCLA-128
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Zenocutuzumab
CAS Number: 1969309-56-5
Current Sponsor code: MCLA-128
Other descriptive name: A bispecific humanized full length IgG1 antibody with enhanced ADCC
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Primary end point(s): Part 1:
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)

Part 2: Group A-E:
- Frequency and nature of AEs
- Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST v1.1 as per local Investigator's assessment. The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored, and serum biomarkers such as CA-125 (ovarian, endometrial) and CA 19-9 (gastric)

Part 2: Groups F, G, H (NRG1 fusion)
- Overall response rate (ORR) per RECIST v1.1 as per local investigator's assessment.
- Duration of response per RECIST v1.1 as per local Investigator's assessment

Main Objective: Part 1:
- Determination of MTD/MRD and tolerability

Part 2: Group A-E:
- To characterize the safety and tolerability of MCLA-128
- To explore the relationships between the anti-tumor activity of MCLA128 and disease-related biomarkers

Part 2: Groups F, G, H (NRG1 fusion)
- To assess the magnitude of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally
- To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed locally

Secondary Objective: Part 1:
- safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128.
- Evaluation of anti-tumor response and CBR.

Part 2 Groups A-E:
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of PFS and overall survival, duration of response

Part 2: Groups F, G, H (NRG1 fusion)
- To assess the magnitude of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed centrally
- To assess the clinical benefit rate (CBR) of MCLA-128 in patients with NRG1 fusions as assessed locally and centrally
- To assess durability of anti-tumor activity of MCLA-128 in patients with NRG1 fusions as assessed centrally
- To assess time to onset of response in patients with NRG1 fusions as assessed locally and centrally
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128
- Evaluation of progression-free survival and overall survival

Timepoint(s) of evaluation of this end point: Part 1:
- Continuous assessment of AEs

Part 2 A-E:
- Continuous assessment of AEs
- Every 8 weeks until end of treatment (ORR, DOR, CBR)
- Pre-dose Cycle 1 Day, Cycle 2 D1. Every 2 cycles therafter (biomarkers)

Part 2 F,G,H:
- Every 8 weeks until end of treatment

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Part 1:
1 Continuous AEs assessment
2 Pre-dose C1D1, EOI; 2,4,24h post EOI, pre-dose & EOI on D15 Cycles
2&3:pre-dose & EOI D1,15. C4 & every 2 cycles thereafter pre-dose D1
3 D1 pre-dose C1,2,3,&4. Every fourth cycle thereafter & EOT & Final visit
4 Every 8 wks til EOT
Part 2 A-E:
5,6 Pre-dose C1D1, EOI; 2,4,24 h post EOI, pre-dose & EOI on D15.C2&3:pre-dose & EOI D1,15. C4 & every2 cycles thereafter pre-dose D1
7 D1 pre-dose for C1,2,3,&4. Every fourth cycle thereafter & EOT & Final visit
Part 2 F, G, H:
8-13 Every 8 wks til EoT
14 Continuous AEs assessment
15 16 Pre-dose C1D1, EOI; 2,4,24 h post EOI, pre-dose & EOI on D15.Cycles 2&3:pre-dose & EOI D1,15. C4,6,8 pre-dose D1
17 D1 pre-dose for C1,2,3,4&8

Secondary end point(s): Part 1:
1 Frequency and nature of AEs/serious adverse events (SAEs)
2 Assessment of PK variables, including total exposure, maximum concentration (Cmax) clearance, volume of distribution (V), volume of distribution at steady state (Vss), half-life (t1/2), AUC0-t (area under the concentration versus time curve from time zero to time t), AUC0-8 (area under the concentration versus time curve), tmax (time to reach maximum concentration)
3 Incidence and serum titers of anti-drug antibodies against MCLA-128
4 Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and survival; CBR is defined 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 12 weeks).

Part 2: Groups A - E:
5 Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-8, tmax
6 Population PK analysis
7 Incidence and serum titers of anti-drug antibodies against MCLA-128

Part 2: Groups F, G, H (NRG1 fusion):
8 Overall response rate per RECIST v1.1 as per central review.
9 CBR (defined as the proportion of patients with a CR or PR, or an SD of a minimum duration of 24 weeks) per RECIST v1.1 as per local Investigator's assessment.
10 CBR per RECIST v1.1 as per central review.
11 Duration of response per RECIST v1.1 as per central review.
12 Time to response per RECIST v1.1. as per local Investigator's assessment.
13 Time to response per RECIST v1.1 as per central review.
14 Frequency and nature of AEs
15 Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-8, tmax
16 Population PK analysis
17 Incidence and serum titers of anti-drug antibodies against MCLA-128.

Secondary ID(s)

2014-003277-42-ES

MCLA-128-CL01

Source(s) of Monetary Support

Merus N.V.

Ethics review

Status: Approved
Approval date: 09/03/2015
Contact: