A Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors
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| ClinicalTrials.gov Identifier: NCT03526835 |
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Recruitment Status :
Recruiting
First Posted : May 16, 2018
Last Update Posted : February 28, 2023
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Advanced/Metastatic Solid Tumors Colorectal Cancer Gastric Cancer Gastroesophageal-junction Cancer NSCLC HNSCC | Drug: MCLA-158 | Phase 1 Phase 2 |
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).
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 360 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase 1/2 Dose Escalation and Cohort Expansion Study Evaluating Single-agent MCLA-158 in Metastatic Colorectal Cancer and Other Advanced Solid Tumors |
| Actual Study Start Date : | May 2, 2018 |
| Estimated Primary Completion Date : | June 2023 |
| Estimated Study Completion Date : | June 2024 |
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: MCLA-158
full-length IgG1 bispecific antibody targeting EGFR and LGR5
Other Name: bispecific |
- Escalation: Number of patients with Dose Limiting Toxicities (DLTs) [ Time Frame: 6-12 months ]Evaluation of number of participants with treatment related toxicities observed during the dose escalation.
- Escalation: Severity of Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]Evaluation of the severity of treatment related toxicities observed during the dose escalation.
- Expansion: Objective overall response rate (ORR) [ Time Frame: 36 months ]Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)
- Escalation & Expansion: Incidence of anti-drug antibodies against MCLA-158 [ Time Frame: 36 months ]Number of participants with anti-drug antibodies against MCLA-158
- Escalation & Expansion: Serum titers of anti-drug antibodies [ Time Frame: 36 months ]Serum titers of anti-drug antibodies against MCLA-158
- Escalation & Expansion: Cytokine Panel Expression Profile [ Time Frame: 36 months ]Evaluation of the cytokine expression profile
- Escalation & Expansion: Biomarkers for EGFR activation and signaling [ Time Frame: 36 months ]Evaluation of biomarker results for EGFR activation and signaling
- Escalation & Expansion: EGFR expression [ Time Frame: 36 months ]Biomarkers in tumor samples relevant to EGFR expression in relation to early tumor response profile of MCLA-158
- Escalation & Expansion: LGR5 expression [ Time Frame: 36 months ]Biomarkers in tumor samples relevant to LGR5 expression in relation to early tumor response profile of MCLA-158
- Escalation & Expansion: Duration of response (DOR) [ Time Frame: 36 months ]Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)
- Escalation & Expansion: Progression Free Survival (PFS) and survival [ Time Frame: 36 months ]Evaluation of clinical benefit assessed by RECIST v1.1 determining objective progression free survival (PFS) and/or survival
- Escalation & Expansion: End of infusion (EOI) plasma concentration [Ceoi] [ Time Frame: 36 months ]End of infusion (EOI) plasma concentration [Ceoi] as measured from all individual plasma concentrations
- Escalation & Expansion: Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]Maximum plasma concentration as measured from all individual plasma concentrations
- Escalation & Expansion: Plasma concentration at 0 hours [C0h] [ Time Frame: 36 months ]Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations
- Escalation & Expansion: Area under the concentration versus time curve from time zero to time t [AUC0-t] [ Time Frame: 36 months ]Area under the concentration versus time curve from time zero to time t [AUC0-t]
- Escalation & Expansion: Area under the concentration versus time curve [AUC0-∞] [ Time Frame: 36 months ]Area under the concentration versus time curve [AUC0-∞]
- Escalation & Expansion: Clearance of plasma [CL] [ Time Frame: 36 months ]Clearance of plasma [CL]
- Escalation & Expansion: Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]Volume of distribution at steady state [Vss]
- Escalation & Expansion: Time to reach maximum concentration [tmax] [ Time Frame: 36 months ]Time to reach maximum concentration [tmax]
- Escalation & Expansion: Half-life [t1/2] [ Time Frame: 36 months ]Half-life [t1/2]
- Expansion: Number of Participants with abnormal laboratory test results [ Time Frame: up to 30 days post last dose ]
- Expansion: Frequency of Treatment-Related Adverse Events (AE) [ Time Frame: 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) [ Time Frame: up to 30 days post-last dose ]Evaluation of the severity of AEs that are related to treatment as assessed by CTCAE version 4.03
- Expansion: Number of participants with abnormal vital signs [ Time Frame: up to 30 days post-last dose ]
- Expansion: Frequency of dose interruptions and reductions [ Time Frame: up to 30 days post-last dose ]Evaluation of the number of dose interruptions and reductions
- Escalation & Expansion: Overall survival (OS) [ Time Frame: 36 months ]Evaluation of clinical benefit assessed by RECIST v1.1 determining overall survival (OS)
- Escalation & Expansion: Biomarkers for Wnt signaling proteins [ Time Frame: 36 months ]Evaluation of biomarker results for Wnt signaling proteins
- Escalation & Expansion: Biomarkers for genetic aberrations in ctDNA [ Time Frame: 36 months ]Evaluation of biomarker results in genetic aberrations in ctDNA
- Escalation & Expansion: Biomarkers for differential expression of miRNA [ Time Frame: 36 months ]Evaluation of biomarker results for differential expression of miRNA
- Escalation & Expansion: Biomarkers for differential expression of mRNA [ Time Frame: 36 months ]Evaluation of biomarker results for differential expression of mRNA
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03526835
| Contact: Eduardo Pennella, MD | +1 617 401 4499 | USenquiries@merus.nl | |
| Contact: Ernesto Wasserman, MD | +1 617 401 4499 | USenquiries@merus.nl |
| United States, California | |
| UCSD | Recruiting |
| La Jolla, California, United States, 92093 | |
| Contact: Shumei Kato, MD smkato@health.ucsd.edu | |
| Principal Investigator: Shumei Kato, MD | |
| United States, Tennessee | |
| Sarah Cannon Research Institute | Completed |
| Nashville, Tennessee, United States, 37203 | |
| Belgium | |
| Institut Jules Bordet | Recruiting |
| Brussels, Belgium | |
| Contact: Christiane Jungels, MD + 32 2 541 31 11 christiane.jungels@bordet.be | |
| Principal Investigator: Christiane Jungels, MD | |
| France | |
| Hopital Saint Andre, CHU Bordeaux | Recruiting |
| Bordeaux, France | |
| Contact: Amaury Daste, MD amaury.daste@chu-bordeaux.fr | |
| Principal Investigator: Amaury Daste, MD | |
| Centre Leon Berard | Recruiting |
| Lyon, France | |
| Contact: Jerome Fayette, MD jerome.fayette@lyon.unicancer.fr | |
| Principal Investigator: Jerome Fayette, MD | |
| Hopital La Timone | Recruiting |
| Marseille, France | |
| Contact: Sebastien Salas, MD sebastien.salas@ap-hm.fr | |
| Principal Investigator: Sebastien Salas, MD | |
| Centre Antoine Lacassagne | Recruiting |
| Nice, France | |
| Contact: Esma Saada-Bouzid, MD esma.saada-bouzid@nice.unicancer.fr | |
| Principal Investigator: Esma Saada-Bouzid, MD | |
| Institut Curie | Recruiting |
| Paris, France | |
| Contact: Christophe Le Tourneau, MD christophe.letourneau@curie.fr | |
| Principal Investigator: Christophe Le Tourneau, MD | |
| Institut Gustave Roussy | Recruiting |
| Paris, France | |
| Contact: Antoine Hollebecque, MD +33 1 42 11 43 85 antoine.hollebecque@gustaveroussy.fr | |
| Principal Investigator: Antoine Hollebecque, MD | |
| Spain | |
| Vall d'Hebron | Recruiting |
| Barcelona, Spain | |
| Contact: Josep Tabernero, MD jtabernero@vhio.net | |
| Principal Investigator: Josep Tabernero, MD | |
| Hospital 12 de Octubre | Recruiting |
| Madrid, Spain | |
| Contact: Rocio Carbonero, MD rgcarbonero@gmail.com | |
| Principal Investigator: Rocio Carbonero, MD | |
| Clinica Universidad de Navarra | Recruiting |
| Pamplona, Spain | |
| Contact: Jose Lopez-Picazo, MD jlpicazo@unav.es | |
| Principal Investigator: Jose jlpicazo@unav.es, MD | |
| Complejo Hospitalario de Navarra | Recruiting |
| Pamplona, Spain | |
| Contact: Virginia Arrazubi, MD | |
| Principal Investigator: Virginia Arrazubi, MD | |
| United Kingdom | |
| Cambridge University Hospitals NHS Foundation Trust | Recruiting |
| Cambridge, United Kingdom | |
| Contact: Elizabeth Smyth, MD elizabeth.smyth2@nhs.net | |
| Principal Investigator: Elizabeth Smyth, MD | |
| Sarah Cannon Research Institute | Recruiting |
| London, United Kingdom | |
| Contact: Elisa Fontana, MD | |
| Contact Elisa.Fontana@hcahealthcare.co.uk | |
| Principal Investigator: Elisa Fontana | |
| Study Director: | Eduardo Pennella, MD | Merus N.V. |
| Responsible Party: | Merus N.V. |
| ClinicalTrials.gov Identifier: | NCT03526835 |
| Other Study ID Numbers: |
MCLA-158-CL01 2017-004745-24 ( EudraCT Number ) |
| First Posted: | May 16, 2018 Key Record Dates |
| Last Update Posted: | February 28, 2023 |
| Last Verified: | February 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Bispecific antibody First-in-human MCLA-158 Antibodies Bispecific |
immunologic factors Cytokines EGFR LGR5 |
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Colorectal Neoplasms Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site |
Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases |