A Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors

Sponsor

Merus N.V. (Industry)

Overall Status

Unknown status

CT.gov ID

NCT03526835

Collaborator

Chiltern International Inc. (Industry), Q2 Solutions (Industry), Oncology Therapeutic Development (OTD) (Other), 4Clinics (Other)

120

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase I, open-label, multi-center, multi-national, dose escalation, single agent study to determine the recommended Phase II dose (RP2D) of MCLA-158 in metastatic colorectal cancer (mCRC). The study will assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of MCLA-158 in mCRC and other advanced solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Advanced/Metastatic Solid Tumors Colorectal Cancer	Drug: MCLA-158	Phase 1

Detailed Description

Study Design:

This open label, multicenter, first-in-human study consists of 2 parts. Part 1 is a dose escalation to find the recommended Phase II dose (RP2D) of MCLA-158 studying patients with metastatic colorectal cancer. Part 2 is a dose expansion cohort studying MCLA-158 in colorectal cancer and other solid tumor indications.

In the dose escalation part, patients with metastatic colorectal cancer previously treated with up to 4 lines of prior therapy in the metastatic setting including oxaliplatin-based and irinotecan-based chemotherapy, with or without an anti-angiogenic and with or without an anti-EGFR if RAS wild-type (RASwt).

In the expansion part, MCLA-158 will be administered at the RP2D in metastatic colorectal patients and selected non-colorectal indications in advanced solid tumors. The expansion part will further characterize the safety, PK, immunogenicity and preliminary antitumor activity of single-agent MCLA-158 will be in all patients, and retrospective biomarker analyses including EGFR and LGR5 status will be performed.

The study consists of three periods: Screening (up to 28 days prior to the first dose of study drug); Treatment (first dose of study drug with treatment cycles of 28 days); and Follow-up (through 30 days after the last dose and and quarterly checks for survival data up to 12 months).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1 Dose Finding Study Evaluating the Bispecific Antibody MCLA-158 in Metastatic Colorectal Cancer and Other Advanced Solid Tumors

Actual Study Start Date :

May 2, 2018

Anticipated Primary Completion Date :

Jan 1, 2021

Anticipated Study Completion Date :

Jan 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MCLA-158 In Part 1, the dose escalation phase, patients with metastatic CRC will receive escalating doses of MCLA-158 (every 2 weeks) until MTD or RP2D is reached. Each Cycle is 28 days. Single agent treatment. In Part 2, the expansion phase, participants with metastatic CRC and certain other solid tumors will receive intravenous infusion of MCLA-158 at the recommended Phase II dose (RP2D) every 2 weeks, at Day 1 and Day 15. The duration of each treatment cycle is 28 days.	Drug: MCLA-158 full-length IgG1 bispecific antibody targeting EGFR and LGR5 Other Names: bispecific

Arm

Intervention/Treatment

Experimental: MCLA-158

In Part 1, the dose escalation phase, patients with metastatic CRC will receive escalating doses of MCLA-158 (every 2 weeks) until MTD or RP2D is reached. Each Cycle is 28 days. Single agent treatment. In Part 2, the expansion phase, participants with metastatic CRC and certain other solid tumors will receive intravenous infusion of MCLA-158 at the recommended Phase II dose (RP2D) every 2 weeks, at Day 1 and Day 15. The duration of each treatment cycle is 28 days.

Drug: MCLA-158

full-length IgG1 bispecific antibody targeting EGFR and LGR5

Other Names:

bispecific

Outcome Measures

Primary Outcome Measures

Number of patients with Dose Limiting Toxicities (DLTs) [6-12 months]
Evaluation of number of participants with treatment related toxicities observed during the dose escalation.
Severity of Dose Limiting Toxicities (DLT) [6-12 months]
Evaluation of the severity of treatment related toxicities observed during the dose escalation.
Expansion: Frequency of Treatment-Related Adverse Events (AE) [up to 30 days post-last dose]
Evaluation of the number of participants with AEs or SAEs that are related to treatment as assessed by CTCAE version 4.03
Expansion: Severity of Treatment-Related Adverse Events (AE) [up to 30 days post-last dose]
Evaluation of the severity of abnormal laboratory values and/or AEs that are related to treatment as assessed by CTCAE version 4.03
Expansion: Changes in laboratory values [up to 30 days post last dose]
Evaluation of the changes between baseline and post-baseline laboratory parameters.
Expansion: Changes in vital signs [up to 30 days post-last dose]
Evaluation of the changes between baseline and post-baseline vital sign values
Expansion: Frequency of dose interruptions and reductions [up to 30 days post-last dose]
Evaluation of the number of dose interruptions and reductions

Secondary Outcome Measures

Incidence of anti-drug antibodies against MCLA-158 [36 months]
Number of participants with anti-drug antibodies against MCLA-158
Serum titers of anti-drug antibodies [36 months]
Serum titers of anti-drug antibodies against MCLA-158
Cytokine Panel Expression Profile [36 months]
Evaluation of the cytokine expression profile
Biomarkers for EGFR activation and signaling [36 months]
Evaluation of biomarker results for EGFR activation and signaling
Biomarkers for resistance to EGFR therapies [36 months]
Evaluation of biomarker results for resistance to EGFR therapies
Biomarkers for Wnt signaling in CTCs, proteins, ctDNA, and miRNA [36 months]
Evaluation of biomarker results for Wnt signaling in CTCs, proteins, ctDNA, and miRNA
Objective overall response rate (ORR) [36 months]
Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
Duration of response (DOR) [36 months]
Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)
Progression Free Survival (PFS) and survival [36 months]
Evaluation of clinical benefit assessed by RECIST v1.1 determining objective progression free survival (PFS) and/or survival
End of infusion (EOI) plasma concentration [Ceoi] [36 months]
End of infusion (EOI) plasma concentration [Ceoi] as measured from all individual plasma concentrations
Maximum plasma concentration [Cmax] [36 months]
Maximum plasma concentration as measured from all individual plasma concentrations
Plasma concentration at 0 hours [C0h] [36 months]
Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations
Area under the concentration versus time curve from time zero to time t [AUC0-t] [36 months]
Area under the concentration versus time curve from time zero to time t [AUC0-t]
Area under the concentration versus time curve [AUC0-∞] [36 months]
Area under the concentration versus time curve [AUC0-∞]
Clearance of plasma [CL] [36 months]
Clearance of plasma [CL]
Volume of distribution at steady state [Vss] [36 months]
Volume of distribution at steady state [Vss]
Time to reach maximum concentration [tmax] [36 months]
Time to reach maximum concentration [tmax]
Half-life [t1/2] [36 months]
Half-life [t1/2]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally disease not amenable to standard therapy with curative intent with patients with metastatic colorectal cancer treated in the metastatic setting with standard approved therapy including oxaliplatin, irinotecan and fluoropyrimidines (5-FU and/or capecitabine) ± an anti-angiogenic agent ± an anti-EGFR agent.
A baseline fresh tumor sample (FFPE and if sufficient material also frozen) from a metastatic or primary site.
Measurable disease as defined by RECIST version 1.1 by radiologic methods.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Life expectancy ≥ 12 weeks, as per investigator.
Adequate organ function

Exclusion Criteria:

Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 14 days of study entry.
Known leptomeningeal involvement.
Participation in another clinical trial or treatment with any investigational drug within 4 weeks prior to study entry.
Any systemic anticancer therapy within 4 weeks or 5 half-lives whichever is longer of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity ( e.g. mitomycin C,nitrosoureas), or anticancer immunotherapies, a washout period of 6 weeks is required.
Requirement for immunosuppressive medication (e.g. methotrexate, cyclophosphamide)
Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible, irrespective of when it was received.
Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 NCI-CTCAE v4.03 is allowed.
History of hypersensitivity reaction or any toxicity attributed to human proteins or any of the excipients that warranted permanent cessation of these agents.
Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) with appropriate treatment or unstable angina.
History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia).
History of myocardial infarction within 6 months of study entry.
History of prior malignancies with the exception of excised cervical intraepithelial neoplasia or nonmelanoma skin cancer, or curatively treated cancer deemed at low risk for recurrence with no evidence of disease for at least 3 years.
Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy.
Patients with a history of interstitial lung disease (e.g.: pneumonitis or pulmonary fibrosis) or evidence of ILD on baseline chest CT scan.
Current serious illness or medical conditions including, but not limited to uncontrolled active infection,clinically significant pulmonary, metabolic or psychiatric disorders.
Active HIV, HBV, or HCV infection requiring specific treatment.
Pregnant or lactating women; patients of childbearing potential must use highly effective contraception methods prior to study entry, for the duration of study participation, and for 6 months after the last dose of MCLA-158.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
2	Institut Jules Bordet	Brussels		Belgium
3	Institut Gustave Roussy	Paris		France
4	Vall d'Hebron	Barcelona		Spain