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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03526835
Recruitment Status : Recruiting
First Posted : May 16, 2018
Last Update Posted : August 13, 2018
Sponsor:
Collaborators:
Chiltern International Inc.
Q2 Solutions
Oncology Therapeutic Development (OTD)
4Clinics
Information provided by (Responsible Party):
Merus N.V.

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).

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


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 Name: bispecific




Primary Outcome Measures :
  1. 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.

  2. Severity of Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]
    Evaluation of the severity of treatment related toxicities observed during the dose escalation.

  3. 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

  4. Expansion: Severity of Treatment-Related Adverse Events (AE) [ Time Frame: 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

  5. Expansion: Changes in laboratory values [ Time Frame: up to 30 days post last dose ]
    Evaluation of the changes between baseline and post-baseline laboratory parameters.

  6. Expansion: Changes in vital signs [ Time Frame: up to 30 days post-last dose ]
    Evaluation of the changes between baseline and post-baseline vital sign values

  7. 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


Secondary Outcome Measures :
  1. Incidence of anti-drug antibodies against MCLA-158 [ Time Frame: 36 months ]
    Number of participants with anti-drug antibodies against MCLA-158

  2. Serum titers of anti-drug antibodies [ Time Frame: 36 months ]
    Serum titers of anti-drug antibodies against MCLA-158

  3. Cytokine Panel Expression Profile [ Time Frame: 36 months ]
    Evaluation of the cytokine expression profile

  4. Biomarkers for EGFR activation and signaling [ Time Frame: 36 months ]
    Evaluation of biomarker results for EGFR activation and signaling

  5. Biomarkers for resistance to EGFR therapies [ Time Frame: 36 months ]
    Evaluation of biomarker results for resistance to EGFR therapies

  6. Biomarkers for Wnt signaling in CTCs, proteins, ctDNA, and miRNA [ Time Frame: 36 months ]
    Evaluation of biomarker results for Wnt signaling in CTCs, proteins, ctDNA, and miRNA

  7. Objective overall response rate (ORR) [ Time Frame: 36 months ]
    Evaluation of clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR)

  8. Duration of response (DOR) [ Time Frame: 36 months ]
    Evaluation of clinical benefit assessed by RECIST v1.1 determining duration of response (DOR)

  9. 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

  10. 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

  11. Maximum plasma concentration [Cmax] [ Time Frame: 36 months ]
    Maximum plasma concentration as measured from all individual plasma concentrations

  12. Plasma concentration at 0 hours [C0h] [ Time Frame: 36 months ]
    Plasma concentration at 0 hours [C0h] as measured from all individual plasma concentrations

  13. 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]

  14. Area under the concentration versus time curve [AUC0-∞] [ Time Frame: 36 months ]
    Area under the concentration versus time curve [AUC0-∞]

  15. Clearance of plasma [CL] [ Time Frame: 36 months ]
    Clearance of plasma [CL]

  16. Volume of distribution at steady state [Vss] [ Time Frame: 36 months ]
    Volume of distribution at steady state [Vss]

  17. Time to reach maximum concentration [tmax] [ Time Frame: 36 months ]
    Time to reach maximum concentration [tmax]

  18. Half-life [t1/2] [ Time Frame: 36 months ]
    Half-life [t1/2]



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

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


Contacts
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Contact: Ernesto Wasserman, MD +31302538800 enquiries@merus.nl
Contact: Andres Sirulnik, MD PhD +31302538800 enquiries@merus.nl

Locations
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United States, Tennessee
Sarah Cannon Research Institute Not yet recruiting
Nashville, Tennessee, United States, 37203
Contact: Johanna Bendell, MD    615-329-7274    jbendell@tnonc.com   
Principal Investigator: Johanna Bendell, MD         
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
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: Guillem Argiles, MD    +34 93 274 60 85    garguiles@vhio.net   
Principal Investigator: Guillem Argiles, MD         
Sponsors and Collaborators
Merus N.V.
Chiltern International Inc.
Q2 Solutions
Oncology Therapeutic Development (OTD)
4Clinics
Investigators
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Study Director: Ernesto Wasserman, MD Merus N.V.
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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: August 13, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data are made available only to the individual patient upon specific request of that individual patient or its treating physician.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merus N.V.:
Bispecific antibody
First-in-human
MCLA-158
Antibodies
Bispecific
immunologic factors
Cytokines
EGFR
LGR5
Additional relevant MeSH terms:
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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