advanced solid tumors
Conditions
Interventions
INVESTIGATIONAL THERAPY AND REGIMEN MCLA-158: IV infusion every 2 weeks, with a
starting dose of 5 mg (flat dose). The following dose levels were planned: 5,
20, 50, 90, 150, 225, 335, 500, 750, 110
Sponsors
Merus N.V.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Signed ICF before initiation of any study procedures 2. Age >=18 years at signing of ICF 3. Histologically or cytologically confirmed solid tumors with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent: • Expansion cohorts: patients with locally advanced unresectable or metastatic disease for the following indications: SINGLE AGENT o 2L/3L HNSCC PATIENTS: patients who have progressed on or after, or are intolerant to, anti-PD-(L)1 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 should not have received more than 2 prior lines of treatment in recurrent or metastatic disease. * Human papillomavirus (HPV) status determined by p16 IHC or molecular HPV test for all oropharyngeal tumors should be reported when available. * The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. o Cancers of the anogenital tract with squamous cell histology (ie, cervical, vaginal, vulvar, penile, anal) o Skin SCC o NSCLC non-SCC and NSCLC SCC o GEA with histologically confirmed EGFR amplification (fluorescence in situ hybridization [FISH] score EGFR/ chromosome 7 (CEP7) ratio >=2.0, or tumor NGS EGFR copy >=8, or ctDNA >=4, or EGFR IHC H-score >=200) o PA o mCRC in 3L+: Patients should be free of mutations in RAS family genes (i.e. KRAS, NRAS, Harvey Rat Sarcoma virus [HRAS], or RAF family genes (i.e. BRAF, A-Rapidly Accelerated Fibrosarcoma [ARAF}, Rapidly Accelerated Fibrosarcoma-1 [RAF1]), determined by central ctDNA NGS prescreening]). Note: If the patient was treated with an EGFR inhibitor in 1L or 2L, then the patient should have shown CR/PR. In addition, the patient at study entry should have at least 6 months of interval since the last administration of EGFR inhibitor. Other indications may be considered, such as malignant salivary gland tumors. • Note 1: Patients with NSCLC must receive all recommended standard therapies driven by the histological subtype and tumor molecular profile. • Note 2: 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. COMBINATION o 1L HNSCC: patients eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS >=1, as determined by an 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 advance 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. o 2L mCRC: Patients should have been previously diagnosed with histologically or cytologically confirmed unresectable o
Exclusion criteria
Exclusion criteria: 1. 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 2. Known leptomeningeal involvement 3. Participation in another clinical trial or treatment with any investigational drug within 4 weeks prior to study entry 4. 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 (eg, mitomycin C, nitrosoureas), or anticancer immunotherapies, a washout period of 6 weeks is required. 5. Requirement for immunosuppressive medication (eg, methotrexate, cyclophosphamide) 6. 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. 7. Persistent Grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy Grade 150 mmHg and/or diastolic BP >100 mmHg) with appropriate treatment; 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); or history of myocardial infarction within 6 months of study entry 10. 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. 11. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy, including patients with a history of ILD (eg, pneumonitis or pulmonary fibrosis), or evidence of ILD on baseline chest computerized tomography (CT) scan 12. Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic, or psychiatric disorders 13. Patients with known infectious diseases: • Active hepatitis B infection (hepatitis B surface antigen [HbsAg] positive) without receiving antiviral treatment. Note: o Patients who are HbsAg positive must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral agents, starting at least >=7 days before the initiation of study treatment. o Patients with antecedents of hepatitis B (eg, anti-hepatitis B core (anti-HBc) positive, HbsAg, and hepatitis B virus [HBV]-DNA negative) are eligible. • Positive test for hepatitis C virus (HCV) RNA. Note: Patients in whom HCV infection resolved spontaneously (ie, 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 interferon [IFN]-free regimens) or >=12 months (with the use of IFN-based regimen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose escalation: • To determine the preliminary RP2D of single-agent petosemtamab in mCRC patients who have progressed on chemotherapy, with or without an anti-vascular endothelial growth factor (VEGF) therapy, and with an anti-EGFR therapy (if RASwt) Dose expansion (single agent- non-randomized expansion cohorts): • To determine the overall response rate (ORR) per RECIST 1.1 (per investigator review) Dose expansion (single agent, randomized expansion in HNSCC 2/3L): • To descriptively characterize all relevant clinical safety and efficacy data within the study • To characterize the exposure-safety relationship of petosemtamab administered at 1100 mg and 1500 mg Q2W in terms of TEAEs Dose expansion (combination): • To determine the overall response rate (ORR) per RECIST 1.1 (per investigator review) • To characterize safety and tolerability for combinations. Dose expansion (combination, 2L mCRC cohort) • To characterize safety and tolerability for petosemtamab in combination with FOLFIRI/FOLFOX | — |
Secondary
| Measure | Time frame |
|---|---|
| Dose escalation: safety and tolerability PK immunogenicity biomarkers in tumor samples relevant to EGFR and LGR5 and early tumor response profile preliminary antitumor activity Dose exp. (single agent/combination): antitumor activity in terms of PFS, DOR RECIST 1.1 (per investigator) and in exp. cohorts with antitumor activity observed (per central review) OS safety/tolerability of single-agent peto. and confirm the RP2D PK of peto. (single agent) and of peto. in combo with pembro.FOLFOX/FOLFIRI immunogenicity of peto. biomarkers relevant to EGFR and LGR5 and tumor response of peto. Dose exp. (single agent, randomized exp. in HNSCC 2/3L): exposure-efficacy relationship of peto. at 1100 mg and 1500 mg Q2W: sum of lesions and in terms of Grade 3-4 TEAEs, IRRs and non-IRR TEAEs other safety PK immunogenicity antitumor activity: ORR, DOR, PFS RECIST 1.1 (per investigator/centralreview) biomarkers in samples relevant to EGFR and LGR5 as well as the early tumor response profile | — |
Countries
Netherlands
Outcome results
None listed