Acute Myelogenous Leukemia OR Leukemia
Conditions
Interventions
The starting dose level was estimated based on a minimum anticipated biological
effect level (MABEL) approach. The starting dose is 25 *g flat dose (equal to
approximately 0.4 *g/kg). The MTD or the
Sponsors
Merus N.V.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: To be eligible to participate in this study, all candidates must meet all the following criteria: 1. Male or female age *18 years old; 2. Understand and voluntarily sign the informed consent form prior to any study specific screening procedures; 3. One of the two following: i) Documented diagnosis of AML either de novo or secondary [any subtype except acute promyelocytic leukemia (APL)] according to World Health Organization (WHO) classification who either: a) are in relapse to standard therapy following an initial response; b) failed primary induction therapy with no CR (failed *2 courses of intensive induction therapy. Intensive chemotherapy defined as an intensity of * 5+2); c) newly diagnosed untreated AML in patients * 65 years of age with high risk cytogenetics, if they are not candidates for standard available induction chemotherapy; d) AML secondary to MDS, either relapsed or refractory, previously treated with hypomethylating agents for at least 4 cycles; e) Relapsed or refractory AML unfit for intensive chemotherapy previously treated with a low intensity regimen (e.g. low dose Ara-c, hypomethylating agent, etc.) including Venetoclax for at least 2 cycles; Or ii) MDS patients who meet the following criteria: very high-risk disease (IPSS-R score > 6, Greenberg et al., 2012), either relapsed or refractory, previously treated with hypomethylating agents for at least 4 cycles; 4. Baseline BM sample taken by BMA and BMB (unless there is a contraindication) within 28 days prior to first dose of MCLA-117 for CLEC12A detection. In case of a dry tap by BMA a peripheral blood sample will be acceptable; 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 must have resolved to * Grade 1 or baseline before enrollment as defined by NCI-CTCAE version 4.03. Note: alopecia and stable neuropathy (* Grade 2) are allowed; 8. Acceptable laboratory values: a. Serum creatinine * 3.0 × ULN (upper limit of normal); b. Total serum bilirubin * 1.5 × ULN, except for patients with Gilbert syndrome in which case it should be * 3 x ULN; c. Serum aspartate transaminase (AST) and alanine transaminase (ALT) * 2.5 × ULN; d. Serum potassium, magnesium and calcium levels within institutional normal limits; 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 in such a manner that the risk of pregnancy is minimized. WOCBP includes any female that has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not post- menopausal (defined as amenorrhea >12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level > 35 mIU/mL). Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine devi
Exclusion criteria
Exclusion criteria: Candidates will be excluded from study entry if any of the following exclusion criteria exist: 1. Diagnosis of chronic myelogenous leukemia in blast crisis; 2. Prior hematopoietic stem cell transplantation (this exclusion applies for dose escalation Part 1 and Cohort A of Part 2);For patients in Cohort B of Part 2, prior hematopoietic stem cell transplantation if any of the following applies: a) transplant within 60 days b) history of acute GVHD c) evidence of active chronic GVHD d) need for immunosuppressive therapy (refer to exclusion criterion #7) 3. 4. Treatment with anticancer medications, investigational drugs or radiotherapy within the following intervals before the first dose of MCLA-117: a) 14 days or 5 half-lives for anticancer medications or investigational drugs. For agents with long half-lives (e.g., > 5 days), enrollment before the fifth half-life requires medical monitor approval. Note: the concomitant use of hydroxyurea is allowed up to Day 7 (including) during Cycle 1; b) 14 days for radiotherapy. Note: a 1-week washout period is permitted for palliative radiation to non-CNS disease with Sponsor approval; 5. Previous receipt of live vaccines in the 4 weeks prior to study drug administration (Cycle 1 Day 1); 6. Chronic concurrent need for 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 (Cycle 1 Day 1); 8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving intrathecal therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor. The CNS leukemia controlled state should have been documented with at least two consecutive negative spinal fluid assessments and with negative imagining studies if previously positive; 9. Patients who are pregnant or lactating; 10. Patients with an active infection or with an unexplained fever greater than 38.5°C during screening visits or on the first scheduled day of dosing. (At the discretion of the investigator, patients with tumor fever may be enrolled; patients with recent infections should have temperature < 38.5°C for at least 48 hours prior to first administration of MCLA-117); 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. Patients who have previously been treated for HCV and have undetectable viral loads, could be considered eligible for the trial; 13. Patients with NYHA Class III or IV congestive heart failure or known left ventricular ejection fraction (LVEF) < 50%, or significant uncontrolled cardiac disease, current diagnosis of unstable angina, uncontrolled CHF, 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 intent and without evidence of malignant disease for 1 year before screening. Patients with prior he
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Preliminary clinical efficacy will be evaluated according to the international working group revised criteria of response for AML (Cheson et al, 2003). Assessments and assignment of efficacy will be done at investigational sites. Samples of blood and BM will be obtained at Screening and during and post treatment at intervals specified in the study protocol*s schedule of assessments. | — |
Secondary
| Measure | Time frame |
|---|---|
| PK assessments In Part 1 and 2, samples will be collected at pre-specified time points from pre-dose at Day 1 up to 6 days after EOI of Day 22 during cycle 1 and pre-dose and at 5 minutes prior to end-of-infusion (EOI) at Day 1 and Day 15 during all other cycles. PK sampling will be performed by the investigating site. PK sample analysis will be performed at a central laboratory. In case of changes in frequency of administration during the study, timing and number of sampling may be modified per amendment. Cytokine panel In cycle 1 a panel of cytokines will be measured in serum samples obtained pre-infusion and at a number of predefined time points following MCLA-117 administrations. Cytokine sampling will be performed by the investigating site. The analysis of the cytokines will be performed at a central laboratory. Anti-drug antibody assessment (Part 1 and Part 2) Serum titers of anti-MCLA-117 antibodies will be determined pre-dose at Day 1 and at Day 28 of each cycle. Additional sampling within individual patients is allowed if a suspected delayed hypersensitivity reaction is observed. In case ADA blood sampling and MCLA-117 administration are scheduled for the same day, ADA blood sampling should be performed prior to MCLA-117 administration. Anti-drug antibody sampling will be performed by the investigating site and analysis will be performed at a central laboratory. | — |
Countries
Netherlands
Outcome results
None listed