Main info

Identificatie:

HO143 MM

Sponsor:

HOVON

Working group party:

Myeloma

Age:

>= 18

Stadium:

1st lijn

Echelon:

Level D

Included patients:

133

(of 132)

Active sites:

49

(of 50)

Title:

Efficacy and tolerability of ixazomib, daratumumab and low dose dexamethasone (IDd) followed by ixazomib and daratumumab maintenance therapy until progression for a maximum of 2 years in unfit and frail newly diagnosed multiple myeloma patients; an open-label phase II trial.

Timeline

News

Flow

Details

Phase:

Prospective Phase II study

Monitoring Type:

Not any more

Objectives:

Primary objective:

• To determine the efficacy, defined as overall response rate (ORR), of 9 cycles of ixazomib, daratumumab and low dose dexamethasone. Overall response will be defined as (stringent) complete response ((s)CR), very good partial (VGPR) response and partial response (PR)

Secondary objectives:

• To determine the tolerability, defined as discontinuation rate due to treatment related toxicity, of 9 cycles of ixazomib, daratumumab and low dose dexamethasone
• To determine adverse events of CTCAE grade 2-4
• To determine complete response (CR) and very good partial response (VGPR) after 9 induction cycles
• To determine complete response (CR) and very good partial response (VGPR) on protocol
• To determine immunophenotypic complete response after 9 induction cycles
• To determine immunophenotypic complete response on protocol
• To determine the flow Minimal Residual Disease negative complete remission
• To determine the imaging plus flow MRD negative complete remission
• To determine progression free survival (PFS)
• To determine overall survival (OS)
• To determine efficacy of therapy determined as time to response and the time to best response
• To determine the effect of maintenance therapy with ixazomib and daratumumab in terms of improvement of response during maintenance
• To determine the tolerability of maintenance therapy, defined as discontinuation rate due to treatment related toxicity of ixazomib and daratumumab
• To determine time to next treatment
• To determine PFS2
• To evaluate quality of life (QoL)

Exploratory objectives:

• To identify geriatric assessment outcomes that predict feasibility and the toxicity of treatment
• To identify biological markers; sarcopenia and senescence markers, that reflect biological age and that predict feasibility and the toxicity of treatment
• To identify immunological and molecular prognostic markers that predict outcome and toxicity
• To identify biomarkers for response
• To investigate the prognostic value of Minimal Residual Disease
• To investigate the prognostic value of FDG-PET-CT at diagnostics and in follow up

Eligibility

Inclusion Criteria:

• Previously untreated patients with a confirmed diagnosis of multiple myeloma according to IMWG criteria (see protocol appendix A);
• Measurable disease according to the IMWG criteria (see protocol appendix A); (If plasmacytoma is the only measurable parameter, the patient is not allowed to be included in the study, because of difficult response evaluation)
• Patients who are either unfit or frail according to the IMWG criteria (see protocol appendix B);
• Age 18 years or older;
• Absolute neutrophil count (ANC) ≥ 1.0 x109/l and platelet count ≥ 75x109/l; Platelet transfusions and G-CSF to help patients meet eligibility criteria are not allowed;
• Written informed consent, including consent for additional bone marrow and blood sampling and a skin biopsy (with the understanding that consent may be withdrawn by the patient at any time without consequences to future medical care);
• Patient is capable of giving informed consent;
• Negative pregnancy test at study entry (only for women of childbearing potential);
• Male patients and female patients of childbearing potential must agree to use adequate contraception from the time of signing the informed consent form through 90 days after the last dose of study drug (see protocol section 9.4 for details).

Exclusion Criteria:

• Non-secretory MM;
• Plasma cell leukemia;
• Systemic Amyloid Light-chain (AL) amyloidosis;
• Central nervous system involvement;
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent;
• Neuropathy, grade 1 with pain or grade ≥ 2;
• Severe cardiac dysfunction (NYHA classification III-IV, appendix D);
• Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec;
• Chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal;
• Moderate or severe persistent asthma within the past 2 years or currently uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study);
• Significant hepatic dysfunction (total bilirubin ≥ 3 x ULN or transaminases ≥ 5 times normal level) except patients with Gilbert’s syndrome as defined by > 80% unconjugated bilirubin;
• Creatinine clearance <20 ml/min or Calculated Glomerular Filtration Rate [ml/min/1.73m2] <20;
• Patients with active, uncontrolled infections;
• Patients known to be Human Immunodeficiency Virus (HIV)-positive;
• Patients seropositive for hepatitis B, defined by a positive test for hepatitis B surface antigen [HBsAg]. Patients with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Patients seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing;
• Active malignancy other than MM requiring treatment or a malignancy that has been treated with chemotherapy currently affecting bone marrow capacity;
• Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort;
• Pre-treatment with cytostatic drug, immunomodulatory drugs (IMiDs) or proteasome inhibitors. Radiotherapy (provided the involved field is small and there are ≥ 7 days between radiotherapy and administration of ixazomib) or a short course of steroids (e.g. 4 day treatment of dexamethasone 40 mg/day or equivalent) are allowed;
• Major surgery within 14 days before enrollment;
• Any serious medical or psychiatric illness, or familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial;
• Female patients who are lactating.

Registration Details

Participating Sites

= Active hospitals

= Inactive hospitals