MCLA-117 in Acute Myelogenous Leukemia

• ClinicalTrials.gov Identifier: NCT03038230
• Recruitment Status: Unknown
• First Posted: January 31, 2017
• Last Update Posted: August 14, 2018
• Sponsor: Merus N.V.
• Collaborators: CROS NT; LGC Limited; VU University Medical Center; Pharmaceutical Research Associates; Kinesis Pharma B.V.; CSM Europe sa; QPS Netherlands B.V.
• Information provided by (Responsible Party): Merus N.V.

Study Description

Brief Summary:

This is a First-in-Human, single arm, open-label, multi-national study designed to determine the safety, tolerability and preliminary efficacy of MCLA 117.

Condition or disease	Intervention/treatment	Phase
Acute Myelogenous Leukemia; Acute Myeloid Leukemia	Drug: MCLA-117 bispecific antibody	Phase 1

Detailed Description:

Study Design :

This open label, single arm, multinational, first-in-human study consists of 2 parts. Part 1 consists of dose escalation cohorts and Part 2 is a dose expansion cohort.

The study population will include adult AML patients (and all subtypes of AML) with relapse or refractory disease and newly diagnosed elderly untreated AML patients with high risk cytogenetics.

In Part 1, dose escalations cohorts are followed until dose-limiting toxicity (DLT) or a maximum tolerated dose (MTD) or RecommendedPart2Dose (RP2D) is defined. Dose escalation decisions will be made by the Data Review Committee and will be primarily guided by safety data observed through the end of Cycle 1, as well as on-going assessment of safety beyond Cycle 1 in later cohorts.

Part 2 will begin once the MTD or RP2D is determined in Part 1. Part 2 will further characterize the safety, tolerability, Pharmacokinetic (PK), Pharmacodynamic (PD), immunogenicity and to assess preliminary efficacy of MCLA-117. This part will enroll at least 15 evaluable patients (defined as evaluable for first efficacy assessment).

For both parts, the study consists of 3 periods: a Screening period (up to 28 days prior to the first dose of study drug); a Treatment period (first dose of study drug until the last dose of study drug with treatment cycles of 28 days); and a Follow Up period (through 30 days after the last dose and quarterly checks for survival data for up to 1 year). Participants' safety will be monitored throughout the study. Patients will be permitted to receive MCLA-117 beyond Cycle 1 if conditions allow this.

Number of Sites:

Approximately 8 centers in five countries 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Multinational Study of MCLA-117 in Acute Myelogenous Leukemia
• Study Start Date: April 2016
• Estimated Primary Completion Date: December 2018
• Estimated Study Completion Date: December 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: MCLA-117 bispecific antibody; Dose escalation cohorts, with escalating doses of MCLA-117 until MTD or RP2D is reached. The dose is given weekly after initial ramp-up dosing steps. Each Cycle is 28 days. Single agent treatment. Part 2-Expansion Cohort: The RP2D of MCLA-117 is given weekly after initial ramp-up dosing steps. Each Cycle is 28 days. Single agent treatment.	Drug: MCLA-117 bispecific antibody; MCLA-117, a human bispecific IgG antibody which targets CLEC12A and CD3; Other Names: bispecific; human bispecific common light chain; bispecific IgG1 targeting CLEC12A and CD3

Outcome Measures

Primary Outcome Measures :

1. Number of participants with Dose Limiting Toxicities (DLT) [ Time Frame: 28 days ]
   Evaluation of number of participants with treatment related toxicity observed during a dose escalation step for 1 Cycle

Secondary Outcome Measures :

1. Maximum plasma concentration [Cmax] [ Time Frame: Day 22 predose, 5 minutes prior to End of Infusion (EOI), 1h, 2h, 4h, 8h, 24h, 72h, 6 days after EOI ]
   Maximum plasma concentration [Cmax] as measured from all individual plasma concentrations
2. Clearance of plasma [ Time Frame: Day 22 predose, 5 minutes prior to End of Infusion (EOI), 1h, 2h, 4h, 8h, 24h, 72h, 6 days after EOI ]
   Clearance of plasma
3. Volume of distribution at steady state [Vss] [ Time Frame: Day 22 predose, 5 minutes prior to End of Infusion (EOI), 1h, 2h, 4h, 8h, 24h, 72h, 6 days after EOI ]
   Volume of distribution at steady state [Vss]
4. Time to reach maximum plasma concentration [Tmax] [ Time Frame: Day 22 predose, 5 minutes prior to End of Infusion (EOI), 1h, 2h, 4h, 8h, 24h, 72h, 6 days after EOI ]
   Time to reach maximum plasma concentration [Tmax]
5. Half-life [t1/2] [ Time Frame: Day 22 predose, 5 minutes prior to End of Infusion (EOI), 1h, 2h, 4h, 8h, 24h, 72h, 6 days after EOI ]
   Half-life [t1/2] calculated as time from all individual plasma concentrations to reach 50% of maximum concentration
6. Area under the concentration versus time curve from time zero to time t [AUC0-t] [ Time Frame: 1 week ]
   Area under the concentration versus time curve [AUC0-t]
7. Incidence of AntiDrugAntibodies (ADA) against MCLA-117 [ Time Frame: 24 months ]
   Number of participants with ADAs against MCLA-117 as measured in serum
8. Serum titer of ADAs against MCLA-117 [ Time Frame: Day 1 of each cycle ]
   Serum titer of ADAs against MCLA-117 as measured in serum
9. Serum titer of ADAs against MCLA-117 [ Time Frame: Day 28 of each cycle ]
   Serum titer of ADAs against MCLA-117 as measured in serum
10. Cytokine levels [ Time Frame: Cycle 1: Day 1, 4, 8 and 28 at predose, 4h and 24h after end of infusion ]
    Change in profile of cytokine upon administration of MCLA-117 compared to baseline
11. Number of myeloblasts [ Time Frame: Day 1 of every cycle and through study completion, an average of 2 months ]
    number of blasts in peripheral blood and in bone marrow
12. Objective response [ Time Frame: Day 1 of every cycle and through study completion, an average of 2 months ]
    Objective response is assessed by Cheson 2003

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Male or female age ≥18 years old;
2. Signed informed consent form

3. AML either de novo or secondary [any subtype except acute promyelocytic leukemia (APL)] who either:

   1. are in relapse to standard therapy following an initial response
   2. failed primary induction therapy with no CR (failed ≥2 induction attempts) and for whom no other approved therapy is available
   3. newly diagnosed untreated AML in patients ≥ 65 years of age with high risk cytogenetics, if they are not candidates for standard available induction chemotherapy
4. Must have baseline BM sample taken by BMA/BMB within 21 days prior to first dose of MCLA-117 for CLEC12A detection;
5. Estimated life expectancy of at least 8 weeks;
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;
7. Significant toxicities incurred as a result of previous anti-cancer therapy resolved to ≤ Grade 1 (NCI-CTCAE version 4.03);
8. Acceptable laboratory values at screening;
9. Male patients must agree to use an adequate and medically accepted method of contraception throughout the study and for at least 6 months after if their sexual partners are women of child bearing potential (WOCBP).
10. WOCBP must be using highly effective and medically accepted method of contraception to avoid pregnancy throughout the study and for at least 6 months after the study ;
11. WOCBP must have a negative serum or urine pregnancy test within 72 hours prior to the start of study drug.
12. Peripheral blast count </= 30,000/mm3 at the time of initiation of infusion on Cycle 1 Day 1.

Exclusion Criteria:

1. Diagnosis of chronic myelogenous leukemia in blast crisis;
2. Prior hematopoietic stem cell transplantation;
3. Cancer chemotherapy within four weeks prior to start of MCLA-117;
4. Previous treatment with radiotherapy, or immunotherapeutic agents, or receipt of live vaccines in the 4 weeks prior to study drug administration;
5. Previous treatment with any other investigational agents within 4 weeks prior to MCLA-117 administration;
6. Concurrent need of use of corticosteroids > 10 mg/day of oral prednisone or the equivalent, except topical preparations (e.g., topical creams, steroid inhaler, nasal spray or ophthalmic solution);
7. Use of immunosuppressant medications within 4 weeks of MCLA-117 administration;
8. Clinically active central nervous system (CNS) leukemia;
9. Patients who are pregnant or lactating;
10. Patients with an active infection or with an unexplained fever during screening or on the first scheduled day of dosing;
11. Patients with known hypersensitivity to any of the components of MCLA-117 or who have had prior hypersensitivity reactions to human or humanized monoclonal antibodies;
12. Patients with known HIV, hepatitis B or C;
13. Patients with New York Heart Association Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%, or significant uncontrolled cardiac disease, current diagnosis of unstable angina, uncontrolled congestive heart failure, new myocardial infarction, or ventricular arrhythmia requiring medication;
14. Prior malignancy (other than basal cell carcinoma and cervical in situ carcinoma) unless treated with a curative intend and without evidence of malignant disease for 1 year before screening. Patients with prior hematologic malignancies that have progressed to AML (such as Myelodysplastic syndrome, myeloproliferative neoplasms, bi-phenotypic leukemias, AcuteLymphocyticLeukemia) or AML that has relapsed are eligible;
15. Urinary protein >2+ possibly indicative of renal disease. If the 24 hours urine protein shows a result of < 100 mg protein, subject can be eligible;
16. Patients with 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 and participate in the study, or interfere with the interpretation of the results;
17. WOCBP or males with a WOCB partners not willing to use highly effective and medically accepted methods of contraception for 6 months after last study drug administration.
18. Need for concurrent other cytoreductive chemotherapy.

Contacts and Locations

Contacts

Contact: Ernesto Wasserman, MD; +31302538800; enquiries@merus.nl

Contact: Andres Sirulnik, MD, PhD; +31302538800; enquiries@merus.nl

Locations

United States, Massachusetts

Dana Farber Cancer Institute; Not yet recruiting

Boston, Massachusetts, United States, 02215

Contact: Daniel Deangelo

Principal Investigator: Daniel Deangelo, MD

United States, New York

Icahn School of Medicine at Mount Sinai; Not yet recruiting

New York, New York, United States, 10029

Contact: John Mascarenhas, MD

Principal Investigator: John Mascarenhas, MD

United States, Texas

The University of Texas, MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Jorge Cortes, MD

Principal Investigator: Jorge Cortes, MD

Belgium

Ziekenhuis Netwerk Antwerpen Campus Stuivenberg; Recruiting

Antwerpen, Belgium, 2060

Principal Investigator: Dimitri A Breems, MD

France

Institut Gustave Roussy; Recruiting

Villejuif Cedex, Ile-de-France, France, 94805

Contact: Elodie Zedouard

Principal Investigator: Stéphane De Botton, MD

Italy

Fondazione Policlinico Tor Vergata; Recruiting

Rome, Italy, 00133

Contact: Silvia Miccichè +390620903213 silvia.micciche@ptvonline.it

Principal Investigator: Adriano Venditti, MD

Netherlands

Vrije Universiteit Medisch Centrum; Recruiting

Amsterdam, Noord-Holland, Netherlands, 1081HV

Contact: Gert Ossenkoppele, MD

Principal Investigator: Gert Ossenkoppele, MD

Erasmus MC; Recruiting

Rotterdam, Zuid-Holland, Netherlands

Contact: Mojca Jongen-Lavrencic, MD

Principal Investigator: Mojca Jongen-Lavrencic, MD

Universitair Medisch Centrum Groningen; Recruiting

Groningen, Netherlands

Contact: Gerwin Huls, MD

Principal Investigator: Gerwin Huls, MD

Sponsors and Collaborators

Merus N.V.

CROS NT

LGC Limited

VU University Medical Center

Pharmaceutical Research Associates

Kinesis Pharma B.V.

CSM Europe sa

QPS Netherlands B.V.

Investigators

• Principal Investigator: Jorge Cortes, MD, PhD; Independent Protocol Advisor

More Information

• Responsible Party: Merus N.V.
• ClinicalTrials.gov Identifier: NCT03038230
• Other Study ID Numbers: MCLA-117-CL01; 2015-003704-23 ( EudraCT Number )
• First Posted: January 31, 2017
• Last Update Posted: August 14, 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.

Keywords provided by Merus N.V.:

human bispecific full length IgG antibody, CLEC12A, CD3; MCLA-117; First in Human; Antibodies, Bispecific; Immunologic Factors; relapsed, refractory patient; AML, minimal residual disease (MRD); Acute Myelogenous Leukemia; Acute Myeloid Leukemia; CD34+CD38; T-cell recruiting

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Antibodies; Antibodies, Bispecific; Immunologic Factors; Physiological Effects of Drugs