| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Waldenström's macroglobulinemia |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054697 |
| E.1.2 | Term | Waldenstrom's macroglobulinemia recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054698 |
| E.1.2 | Term | Waldenstrom's macroglobulinemia refractory |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For the phase I part: to establish the recommended phase II dose for the combination of oral ixazomib citrate and dexamethasone in patients with WM.
For the phase II part: To assess the efficacy (overall response rate) of oral ixazomib citrate in
combination with rituximab and dexamethasone |
|
| E.2.2 | Secondary objectives of the trial |
For the phase II part:
-To assess the safety of oral ixazomib citrate in combination with rituximab and dexamethasone, followed by rituximab maintenance for 2 years, with special emphasis on neurotoxicity, infections and the incidence of IgM flare requiring plasmapheresis
-To assess the feasibility of oral ixazomib citrate in combination with rituximab and dexamethasone, defined as percentage of patients who complete the full treatment course
- To assess the effect of 2 cycles of oral ixazomib citrate and dexamethasone (before rituximab is added) on M-protein levels
- To assess the improvement of response during rituximab maintenance
- To assess the effect of the treatment on patient reported outcomes
- To perform an exploratory analysis of prognostic markers and markers of disease activity
-To study in vivo the effect of treatment with an oral proteasome inhibitor on sorted WM B- cells and plasma cells from the bone marrow |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- A diagnosis of relapsed or progressive WM (lymphoplasmacytoid lymphoma in the bone marrow with an IgM M-protein)
- Age ≥ 18 years
- WHO 0-2
- Measurable disease (WM M-protein > 10 g/l (1 g/dl)
- Symptomatic disease
- ≥ 1 prior lines of treatment
- Presence of an IgM M-protein in the serum (as demonstrated by SPEP and IF)
- Measurable disease (IgM M-protein > 10 g/l (1 g/dl))or, in case the M-protein is present but unquantifiable, total serum IgM level > 10 g/l (1 g/dl))
- Symptomatic disease (see appendix C)
- Patients showing progressive disease under treatment with chemotherapy only (e.g. chlorambucil, CVP, fludarabine or fludarabine/cyclophosphamide) are allowed on study
- Platelets > 75x10^9/l. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
- ANC >1.0 x10^9/l
- Prior plasmapheresis in case of symptomatic hyperviscosity is allowed
- Negative pregnancy test at study entry for women of childbearing potential
- A female patient is either post-menopausal for at least 1 year before the screening visit, or surgically sterile, or, if of childbearing potential, agrees to practice 2 effective methods of contraception at the same time, from the time of signing the informed consent until 12 months after the last dose of rituximab, or agrees to completely abstain from heterosexual intercourse. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception)
- Male patients, even if surgically sterilized, (i.e., status post vasectomy) must agree to practice effective barrier contraception during the entire study period and through 3 months after the last dose of ixazoimb citrate and/or rituximab, or agree to completely abstain from heterosexual intercourse. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception)
- Written informed consent
- Prior plasmapheresis in case of symptomatic hyperviscosity is allowed |
|
| E.4 | Principal exclusion criteria |
- Bortezomib refractory (no PR/CR after treatment with bortezomib, and/or progression within 6 months of treatment with bortezomib)
- Rituximab refractory (progressive disease during treatment or within 6 months after last administration of rituximab)
- Amyloidosis
- Peripheral neuropathy, grade 3 or higher, or grade 2 with pain on clinical examination during the screening period
- Creatinine clearance <30 ml/min according to the Cockroft&Gault formula (see appendix I)
- Known HIV seropositivity
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or history of HBV infection (patients with serological evidence of current or past HBV exposure are excluded unless the serological findings are clearly due to vaccination)
- History of organ transplantation including allogeneic stem cell transplantation
- Known intolerance of rituximab and/or boron
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- Bing Neel syndrome or other severe neurological disorders
- Severe cardiac dysfunction (NYHA classification III-IV; see appendix H)
- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
- Severe pulmonary dysfunction (CTCAE grade III-IV)
- Significant hepatic dysfunction (defined as total bilirubin >1.5 ULN (unless caused by Gilbert syndrome) and/or transaminases ≥3 times upper limit of normal, unless caused by WM
- Active, uncontrolled infections requiring systemic antibiotic therapy or other serious infections within 14 days before study enrollment
- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, hypertension)
- Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- Major surgery within 14 days of enrollment
- Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administrations of the ixazomib citrate
- Systemic treatment, within 14 days before the first dose of ixazomib citrate, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort
- Breastfeeding
- Current participation in another therapeutic clinical trial (other study medication should have been stopped at least 4 weeks before registration in this trial).
- Failure to have fully recovered (i.e. =< grade 1 toxicity) from the reversible effects of prior chemotherapy
- Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib citrate including difficulty swallowing
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint phase I: dose limiting toxicity of the combination of oral ixazomib citrate and dexamethasone in patients with WM
Primary Endpoint phase II: overall response rate (including CR, VGPR, PR and MR) after 8 cycles of ixazomib citrate, rituximab and dexamethasone, measured at 3 months after start of the last cycle (prior to the start of maintenance) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary end point phase I: after 2 induction cycles
Primary end point phase II: after 8 induction cycles, measured at 3
months after start of the last cycle (prior to the start of maintenance) |
|
| E.5.2 | Secondary end point(s) |
- Rate of CR, VGPR, PR, MR (separately) after 8 cycles
- Best ORR and rate of CR, VGPR, PR, MR on protocol
- Increase in haematocrit after cycle 4 and cycle 8 as compared to baseline
- Effect of 2 cycles of ixazomib citrate and dexamethasone on M-protein levels (% increase or decrease compared to baseline)
- Improvement of response after maintenance treatment
- Time to response and time to best response
- Progression free survival, defined as time from registration to progression/relapse or death from any cause, whichever comes first
- Duration of response
- Time to next treatment
- Overall survival, defined as time from registration to death from any cause. Patients alive will be censored at the date of last contact.
- Toxicity as defined by type, frequency and severity of adverse events according to the NCI Common Terminology Criteria for Adverse Events version 4.0, with special focus on neurotoxicity, infections and the incidence of IgM flare requiring plasmapheresis
- Quality of life
- Feasibility (percentage of patients completing the full treatment course (at least 6 cycles of induction treatment and 2 years of maintenance)) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Respectively after 2, 4, 8 induction cycles and/or after maintenance |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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