A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Partner Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Jan 2015 → ongoing

Decision date (initial)

2024-04-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512358-78-00

EudraCT number

2014-003277-42

ClinicalTrials.gov

NCT02912949

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacogenomic, Pharmacokinetic, Dose response, Safety, Therapy

Part 1:
- Determination of the maximum tolerated dose (MTD) and/or maximum recommended dose (MRD) of MCLA-128.
Part 2: Groups A – E, and F
- To characterize the safety and tolerability of MCLA-128
- To explore the relationships between the anti-tumor activity of MCLA-128 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 objectives 3

1. Part 1: - safety and tolerability of MCLA-128 - Pharmacokinetic profile of MCLA-128 - Immunogenicity of MCLA-128 - Evaluation of anti-tumor response and CBR
2. Part 2 Groups A - E, and F: - PK profile of MCLA-128 - Immunogenicity of MCLA-128 - Evaluation of PFS and overall survival, duration of response
3. 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.

Conditions and MedDRA coding

Solid Tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1. Age ≥18 years
2. 2. ≥1 measurable lesion, RECIST v1.1 or evaluable disease for a limited number of patients in group H
3. 3. ECOG 0, 1 or 2
4. 4. Life expectancy ≥12 weeks
5. 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. 6. Treatment with anti-cancer or investigational product within set intervals before first dose of MCLA-128: 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. 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. 8. Laboratory values at Screenings: a.Absolute neutrophil count ≥1.5 x 10^9/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. e.Estimated glomerular filtration rate (GFR) of >30 mL/min based on the Cockroft-Gault formula.
9. 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: 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. 10. Negative pregnancy test results available as defined by a blood human chorionic gonadotropin (hCG) test during Screening and within 7 days of Cycle 1, Day 1 in women of childbearing potential (defined as women ≤50 years of age or history of amenorrhea for ≤12 months prior to study entry); NOTE: Women with amenorrhea associated with prior treatment with antineoplastic medications are still considered as being of child-bearing potential.
11. 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. 12. Ability to give written, informed consent prior to any study-specific Screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice;
13. 13. Capable of understanding the mandated and optional protocol requirements, is willing and able to comply with the study protocol 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. 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; NOTE – South Korea, Germany and Austria only: patients must have received prior standard therapy appropriate for their tumor type and stage of disease.
15. 15. Histologic or cytologic diagnosis of locally-advanced unresectable or metastatic solid tumor malignancy with a documented NRG1 gene fusion, identified through molecular assays such as RNA/DNA-based sequencing assays, as routinely performed ast CLIA or other similarly-certified laboratories. The following tumor types are included: o Group F: NSCLC o Group G: pancreatic adenocarcinoma o Group H: any other solid tumor NOTE: Patients harboring fusions that are predicted to be non-functional, i.e.., lack of EGF-domain, will not be included in the study. The Sponsor will conduct a review of genomic results and may request collateral testing, approve, or deny the case.

Exclusion criteria 9

1. 1. Pregnant or lactating;
2. 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. 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. 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. 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. 6. Patients with leptomeningeal metastases
7. 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. 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. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1: Evaluation of adverse events (AEs) and dose limiting toxicities (DLT).
2. Part 2: Groups A - E, and F: • Frequency and nature of AEs. • Overall response rate (ORR), Duration of Response (DOR), Clinical Benefit Rate (CBR)
3. Part 2: Groups F, G, H (NRG1 fusion): • ORR per RECIST v1.1 as per local Investigator's assessment. • DOR per RECIST v1.1 as per local Investigator's assessment.

Secondary endpoints 3

1. Part 1: 1. Frequency and nature of AEs/serious adverse events (SAEs). 2. Assessment of PK variables. 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 ORR, DOR, progression-free survival (PFS) and survival.
2. Part 2: Groups A - E, and F : 5. Assessment of PK variables. 6. Population PK analysis. 7. Incidence and serum titers of anti-drug antibodies against MCLA-128.
3. Part 2: Groups F, G, H (NRG1 fusion): ORR per RECIST v1.1. CBR per RECIST v1.1. DOR per RECIST v1.1. Time to response per RECIST v1.1 Frequency and nature of AEs. Assessment of PK variables. Population PK analysis. Incidence and serum titers of anti-drug antibodies against MCLA-128.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Partner Therapeutics Inc.

Sponsor organisation

Partner Therapeutics Inc.

Address

19 Muzzey Street

City

Lexington

Postcode

02421-5256

Country

United States

Scientific contact point

Organisation

Partner Therapeutics Inc.

Contact name

Debasish Roychowdhury

Public contact point

Organisation

Partner Therapeutics Inc.

Contact name

Debasish Roychowdhury

Third parties 10

Locations

10 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

Documents 48 files

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

Application history

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