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About
This is a Phase 1/2 open-label, multi-center, multi-national study with an initial dose escalation part to determine the recommended Phase II dose (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 including head and neck cancer and metastatic colorectal cancer (mCRC).
The study will further assess the safety, tolerability, PK, PD, immunogenicity, and anti-tumor activity of MCLA-158.
Full 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 (mCRC). Enrollment in the dose escalation part has been completed.
In the dose expansion (single-agent cohorts) part of the study, the activity, safety, and tolerability of MCLA-158 at 1500 mg every 2 weeks (Q2W) (preliminary RP2D) as a single agent will be evaluated in cohorts of selected solid tumor indications with dependency on EGFR signaling. The most recently enrolled cohorts were in patients with head and neck squamous cell carcinoma (HNSCC). Enrollment into the HNSCC cohort of single-agent MCLA-158 for the treatment of patients with second/third line (2L/3L) HNSCC is closed. Other closed cohort indications included gastric/gastroesophageal junction adenocarcinoma (GEA) with EGFR amplification and/or high EGFR expression, esophageal carcinoma, and pancreatic adenocarcinoma. In the dose expansion part of the study, safety will also be characterized at two dose levels in this setting.
Additionally, in the dose expansion (combination cohorts) part of the study, the activity, safety, and tolerability of MCLA-158 at 1500 mg Q2W will be evaluated in combination with other therapies. Enrollment in the combination cohort of treatment of MCLA-158 with pembrolizumab for the treatment of patients with first line (1L) HNSCC is closed. A second combination cohort of MCLA-158 with FOLFIRI chemotherapy combination (i.e., 5-fluorouracil [5-FU], leucovorin, and irinotecan (FOLFIRI) will be explored in mCRC (RAS/RAF wild type) patients in the 2L setting. Other expansion cohorts may be considered for combination treatment in the future.
Enrollment
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Inclusion criteria
SINGLE AGENT:
SECOND-/THIRD-LINE HNSCC PATIENTS (cohort closed to enrolment): patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 therapy and platinum therapy as monotherapy or in combination with other agents and no previous exposure to EGFR inhibitors. Patients treated with platinum-containing therapy only in the adjuvant setting, or in the context of multimodal therapy for locally advanced disease should have disease progression within 6 months of the last dose of platinum containing therapy. Patients with no more than 2 prior lines of treatment in recurrent or metastatic disease.
GEA with histologically confirmed EGFR amplification (fluorescence in situ hybridization [FISH] score EGFR/chromosome 7 (CEP7) ratio ≥2.0, or tumor next generation sequencing [NGS] EGFR copy ≥8, or cfDNA ≥2.5, or EGFR IHC H-score ≥200). Cohort closed to enrolment.
Patients with other indications must have been previously treated with 1 or 2 lines of the standard approved therapy (when applicable) in the locally advanced/unresectable or metastatic setting. Other indications may considered such as malignant salivary gland tumors. Cohort closed to enrolment.
COMBINATION:
FIRST-LINE HNSCC (cohort closed to enrolment): patients eligible to receive pembrolizumab as first-line monotherapy with tumors expressing programmed cell death protein ligand 1 (PD-L1), combined positive score (CPS) ≥1, as determined by a Food and Drug Administration (FDA) approved test in the US, or by an approved equivalent test in other countries; patients should not have previous systemic therapy administered in the recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advanced disease is allowed if ended ≥6 months prior to signing the ICF. The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Previous treatments with anti PD-(L)1 or anti-EGFR therapies are not allowed.
2L mCRC (cohort open to enrolment): Patients should have been previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum. Patients must be RAS/RAF WT as determined using NGS on tumor tissue (primary or metastatic) or other appropriate tumor tissue based assay, to be confirmed by the sponsor. Patients must be naive to prior anti-EGFR therapy. Radiographically confirmed disease progression must have occurred during or within 6 months of prior 1L chemotherapy.
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 shorter 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 to any of the excipients of petosemtamab, human proteins or any non-IMP treatment required for this study.
Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg and/or diastolic BP > 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 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 computerized tomography (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 known infectious diseases:
Pregnant or breastfeeding patients; 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.
Primary purpose
Allocation
Interventional model
Masking
567 participants in 3 patient groups
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Central trial contact
Eduardo Pennella, MD; Ernesto Wasserman, MD
Data sourced from clinicaltrials.gov
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