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A Study of MCLA-128 in Patients With Solid Tumors

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ClinicalTrials.gov Identifier: NCT02912949
Recruitment Status : Unknown
Verified March 2017 by Merus N.V..
Recruitment status was:  Recruiting
First Posted : September 23, 2016
Last Update Posted : March 28, 2017
Sponsor:
Collaborators:
Chiltern International Inc.
Covance
LGC Limited
Gustave Roussy, Cancer Campus, Grand Paris
Information provided by (Responsible Party):
Merus N.V.

Brief Summary:
This is a Phase I/II, open-label, multi-center, multi-national, dose escalation, single agent study to assess the safety, tolerability, PK, PD, immunogenicity and anti-tumor activity of MCLA-128

Condition or disease Intervention/treatment Phase
Malignant Solid Tumour Breast Cancer Gastric Cancer Ovarian Cancer Endometrial Cancer Non Small Cell Lung Cancer Drug: MCLA-128 Phase 1 Phase 2

Detailed Description:

Study Design :

This open label (all participants know the identity of the study drug), multicenter (more than one study site), first-in-human study consists of 2 parts. Part 1 is a dose escalation and Part 2 is a dose expansion cohort. Part 1 has been completed.

Part 2 patient populations of interest to receive the RP2D determined in Part 1 are:

  • relapsed/refractory HER2-amplified breast cancer (Group A);
  • advanced/metastatic epithelial ovarian cancer (Group C);
  • advanced/metastatic HER2-amplified gastric cancer or esophageal-gastric junction adenocarcinoma (Group D); .
  • advanced/metastatic endometrial cancer (Group E);
  • advanced/metastatic or recurring HER2 expressing non small cell lung cancer (Group F);

Part 2 will further characterize the safety and tolerability of the selected dose level of MCLA-128, as well as assessment of CBR, defined as the proportion of patients with a CR, PR or durable SD (SD for at least 12 weeks in duration).

The study consists of 3 periods: Screening period (up to 28 days prior to the first dose of study drug); Treatment period (first dose of study drug until the last dose of study drug with treatment cycles of 21 days); and Follow Up period (through 30 days after the last dose and quarterly checks for survival data for up to 2 years). Participants' safety will be monitored throughout the study.

Number of Sites:

Up to 10 sites are estimated to be involved during Parts 1 and 2 of the study. Additional sites may be added to ensure there is an acceptable enrollment rate or to replace non-enrolling/withdrawn sites.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients With Solid Tumors
Actual Study Start Date : January 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Part 1 Dose Escalation
Cohorts receiving escalating doses of MCLA-128 until MTD or RP2D is reached. Each Cycle is 21 days. Single agent treatment.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Experimental: Part 2 breast cancer
Participants will receive intravenous infusion of MCLA-128 at the recommended Phase 2 dose (RP2D) once per cycle. The duration of each treatment cycle is 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Experimental: Part 2 ovarian cancer
Participants will receive intravenous infusion of MCLA-128 at the recommended Phase 2 dose (RP2D) once per cycle. The duration of each treatment cycle is 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Experimental: Part 2 gastric/GE junction cancer
Participants will receive intravenous infusion of MCLA-128 at the recommended Phase 2 dose (RP2D) once per cycle. The duration of each treatment cycle is 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Experimental: Part 2 endometrial cancer
Participants will receive intravenous infusion of MCLA-128 at the recommended Phase 2 dose (RP2D) once per cycle. The duration of each treatment cycle is 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific

Experimental: Part 2 non small cell lung cancer
Participants will receive intravenous infusion of MCLA-128 at the recommended Phase 2 dose (RP2D) once per cycle. The duration of each treatment cycle is 21 days.
Drug: MCLA-128
full length IgG1 bispecific antibody targeting HER2 and HER3
Other Name: bispecific




Primary Outcome Measures :
  1. Number of participants with Dose Limiting Toxicities (DLT) [ Time Frame: 6-12 months ]
    Evaluation of number of participants with treatment related toxicities observed during the dose escalation.

  2. Number of participants with Treatment-Related Adverse Events (AE) [ Time Frame: 6-12 months ]
    Evaluation of number of participants with abnormal laboratory values and/or AE that are related to treatment as assessed by CTCAE version 4.03


Secondary Outcome Measures :
  1. Incidence of Treatment Related AE [safety and tolerability] [ Time Frame: 36 months ]
    Frequency of Treatment Related AEs or SAEs

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

  3. Volume of distribution [V] [ Time Frame: 36 months ]
    volume of distribution [V]

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

  5. half-life [t1/2] [ Time Frame: 36 months ]
    half-life [t1/2]

  6. 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]

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

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

  9. Incidence of anti-drug antibodies against MCLA-128 [ Time Frame: 36 months ]
    Number of participants with anti-drug antibodies against MCLA-128

  10. serum titers of anti-drug antibodies [ Time Frame: 36 months ]
    serum titers of anti-drug antibodies against MCLA-128

  11. Anti-tumor response of MCLA-128 by RECIST v1.1 [ Time Frame: 36 months ]
    Anti-tumor response as measured by RECIST v1.1

  12. Clinical Benefit Rate (CBR) of MCLA-128 [ Time Frame: 36 months ]
    CBR assessed as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks) by RECIST v1.1 .

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

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

  15. 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



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:

  • At least one measurable lesion according to RECIST v1.1;
  • Performance status of ECOG 0 or 1;
  • Estimated life expectancy of at least 12 weeks;
  • Toxicities incurred as a result of previous anti-cancer therapy resolved to ≤Grade 1;
  • At least a 4-week interval since last received radiotherapy;
  • Recovery from major surgery;
  • Absolute neutrophil count ≥1.5 x 109/L without colony stimulating factor support;
  • Platelets ≥100 x 109/L;
  • Hemoglobin ≥9 g/dL or ≥2.2 mmol/L (not transfusion dependent);
  • Total bilirubin <1.5 times the upper limit of normal (ULN);
  • AST (SGOT) ≤2.5 x ULN; ALT (SGPT) ≤2.5 x ULN; ≤5 x ULN for patients with advanced solid tumors with liver metastases; patients with confirmed bony metastases will be permitted on study with isolated elevations in ALP >5 x ULN;
  • Serum creatinine ≤1.5 x ULN or estimated glomerular filtration rate (GFR) of >50 mL/min
  • coagulation function (INR, and aPTT ≤1.5 x ULN , unless on therapeutic anticoagulants);
  • Urine protein ≤ 2+ (as measured by dipstick) or ≤100 mg/24 hours urine
  • Able to provide a tumor biopsy sample (preferably fresh or else archival); if archival: taken within 2 years from screening;
  • Not pregnant or nursing
  • Fertile patients must use effective contraception during and for 6 month after completion of study therapy;
  • Patient with metastatic cancer who has disease progression after having received treatment with all available therapies known to convey clinical benefit

Specific Inclusion Criteria for Part 2 (Group A) breast cancer (BC):

  • Histologically-confirmed and documented advanced / metastatic BC, relapsed/refractory to at least 2 prior HER2 directed regimen for BC;
  • Confirmed HER2 amplification based on historical pathology report or analysis of baseline fresh/archival tumor sample.

Specific Inclusion Criteria for Part 2 (Group C) ovarian cancer (OC):

  • Histologically-confirmed and documented advanced/metastatic epithelial OC for which no curative therapy is available;
  • Prior therapy including all available standard therapies and at least 1 platinum based chemotherapy.

Specific Inclusion Criteria for Part 2 (Group D) gastric or esophageal-gastric junction cancer (GC or GEC):

  • Histologically-confirmed and documented advanced/metastatic GC or GEC ;
  • Prior chemotherapy including platinum and fluoropyrimidine based treatment and trastuzumab
  • Confirmed HER2 amplification based on historical pathology report or analysis of fresh/archival tumor sample.

Specific Inclusion Criteria for Part 2 (Group E) endometrial cancer (EC):

  • Histologically-confirmed and documented advanced/metastatic EC for which no curative therapy is available;
  • Prior therapy including all available standard therapies and at least 1 prior chemotherapy.

Specific Inclusion Criteria for Part 2 (Group F) Non small cell lung cancer (NSCLC):

  • Histologically or cytologically documented diagnosis of Stage IIIB not amenable to radical treatment or Stage IV NSCLC; with pathological characterization of non-squamous or squamous histological subtype and adenocarcinoma subtype classification;
  • Confirmed HER2 expression (by IHC) based on historical pathology report or analysis of baseline (fresh or archival) tumor sample;
  • Prior treatment included all available standard therapies with at least one regimen of platinum-based chemotherapy in locally advanced/metastatic setting/recurrent NSCLC with documented disease progression by investigator assessment;
  • Patients with ALK fusion oncogene with documented disease progression or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the treatment of ALK fusion oncogene NSCLC;
  • Patients with known mutation in the EGFR gene must have documented disease progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant NSCLC.

Exclusion Criteria:

  • Pregnant or lactating;
  • Presence of an active infection or an unexplained fever;
  • Known hypersensitivity to any of the components of MCLA-128;
  • Known HIV, Hepatitis B or Hepatitis C; patients treated for Hepatitis C and have undetectable viral loads are eligible
  • Any untreated central nervous system lesion
  • Patients with leptomeningeal metastases
  • Presence of congestive heart failure or Left Ventricular Ejection Fraction<50% or history of significant cardiac disease, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication.
  • Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative intent more than 2 years prior to study entry;
  • Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results.
  • Prior anti-tumor therapy within 28 days prior to the first scheduled day of dosing with MCLA-128 unless a time interval equal to at least five half-lives of the investigational agent has passed;

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): NCT02912949


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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France
Institut Gustave Roussy Recruiting
Paris, France, 94805
Contact: Elodie Zedouard         
Principal Investigator: Andrea Varga, Dr         
Italy
Niguarda Cancer Centre Recruiting
Milan, Italy, 20162
Contact: Salvatore Siena, Prof         
Contact: Giovanna Marrapese         
Principal Investigator: Salvatore Siena, Prof         
Netherlands
NKI Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Jan Schellens, Prof dr.         
Principal Investigator: Jan Schellens, Prof dr.         
Portugal
Champalimaud Clinical Centre Not yet recruiting
Lisbon, Portugal, 1400-038
Contact: Manuela Seixas, Dr.       manuela.seixas@fundacaochampalimaud.pt   
Principal Investigator: Fatima Cardoso, MD         
Spain
Vall D'Hebron Institute of Oncology (VHIO) Recruiting
Barcelona, Spain, 08035
Contact: Maria Alsina, MD         
Principal Investigator: Josep Tabernero, Prof Dr.         
START Hospital Fundación Jiménez Diaz Recruiting
Madrid, Spain, 28040
Contact: Adriana Armellini         
Principal Investigator: Victor Moreno, Dr.         
START Hospital Universitario Madrid Sanchinarro Recruiting
Madrid, Spain, 28050
Contact: Esther Ordoñez         
Principal Investigator: Emiliano Calvo, Prof. Dr.         
Sponsors and Collaborators
Merus N.V.
Chiltern International Inc.
Covance
LGC Limited
Gustave Roussy, Cancer Campus, Grand Paris
Investigators
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Principal Investigator: Anthony Tolcher, MD Independent protocol advisor

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Responsible Party: Merus N.V.
ClinicalTrials.gov Identifier: NCT02912949     History of Changes
Other Study ID Numbers: MCLA-128-CL01
2014-003277-42 ( EudraCT Number )
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: March 28, 2017
Last Verified: March 2017
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

Keywords provided by Merus N.V.:
Bispecific Antibody IgG1, HER2, HER3
First-in-human
MCLA-128
Antibodies, Bispecific
Immunologic Factors
Cytokines

Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Stomach Neoplasms
Endometrial Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Uterine Diseases
Genital Diseases, Female
Antibodies
Immunoglobulins
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs