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

Phase 1/2 Dose Escalation and Cohort Expansion Study Evaluating Single-agent MCLA-158 in Metastatic Colorectal Cancer and Other Advanced Solid Tumors

This is a Phase 1/2 open-label, multi-center, multi-national study with an initial dose escalation part to determine the RP2D of MCLA-158 single agent in patients with mCRC. The dose escalation part has been completed and the RP2D will be further evaluated in an expansion part of the study. Cohorts of selected solid tumor indications for which there is evidence of EGFR dependency and potential sensitivity to EGFR inhibition will be evaluated. The study will further assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of MCLA-158.

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)) were treated. The dose escalation part has been completed and the RP2D will be further evaluated in the expansion part of the study. 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).

Advanced/Metastatic Solid Tumors, Colorectal Cancer, Gastric Cancer, Gastroesophageal-junction Cancer, NSCLC, HNSCC

Bispecific antibody, First-in-human, MCLA-158, Antibodies, Bispecific, immunologic factors, Cytokines, EGFR, LGR5

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.

Evaluation of number of participants with treatment related toxicities observed during the dose escalation.

Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)

Biomarkers in tumor samples relevant to EGFR expression in relation to early tumor response profile of MCLA-158

Biomarkers in tumor samples relevant to LGR5 expression in relation to early tumor response profile of MCLA-158

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] as measured from all individual plasma concentrations

Escalation & Expansion: Area under the concentration versus time curve from time zero to time t [AUC0-t]

Evaluation of the number of participants with AEs or SAEs that are related to treatment as assessed by CTCAE version 4.03

Inclusion Criteria: Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent. HNSCC patients - Gastric/gastroesophageal junction adenocarcinoma with histologically confirmed EGFR amplification (FISH score EGFR/CEP7 ratio ≥2.0, or NGS EGFR copy ≥8, or cfDNA >2.14, or EGFR IHC H-score ≥200) - NSCLC SCC patients A baseline fresh tumor sample (FFPE) from a metastatic or primary site. Amenable for biopsy. 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. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA). 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. Patients with the following infectious diseases: 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. 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 who 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 t the use of IFN-based regimens) after cessation of antiviral treatment are eligible. Patients with current cirrhotic status of Child-Pugh class B or C; known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 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.