Status and phase
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About
This is a registration, open-label phase 1 study of the combination of ibrutinib/lenalidomide:/dexamethasone in women and men with relapsed/refractory multiple myeloma.
Full description
The study will be completed in two parts: Dose escalation and dose expansion.
Dose Escalation Starting doses of ibrutinib and lenalidomide will be assigned at the time of registration. A minimum of 2 or a maximum of 6 patients will be accrued to a given dose level. Doses will not be escalated in any individual patient.
If none of the first 3 patients treated at a given dose level develops a dose limiting toxicity during the first cycle of treatment, enrollment to the dose level will be closed and enrollment will reopen at next higher dose level. If there are no other higher dose levels to be tested, three additional patients will be enrolled at the current dose level to confirm maximum tolerated dose. If one of the first 3 patients treated at a given dose level develops a dose limiting toxicity during the first cycle of treatment, three additional patients will be enrolled onto the current dose level. If, at any time in the enrollment of these 3 additional patients, a patient develops a dose limiting toxicity, enrollment will be closed to this dose level. Enrollment will be re-opened to the next lower dose level if fewer than 6 patients have been treated at that dose level. If none of these 3 additional patients develops a dose limiting toxicity during the first cycle of treatment, enrollment to this dose level will be closed and enrollment will reopen at next higher dose level. If there are no other higher dose levels to be tested, this will be considered the maximum tolerated dose.
Patients will return to the clinic every 28 days for physical exams, laboratory assessments and review of side effects.
Patients who do not have disease progression and have not experienced unacceptable toxicities will be eligible to continue protocol treatment at their current dose level until disease progression, unacceptable toxicity, or refusal. Those patients who have not experienced progression of disease but have unacceptable toxicity may be eligible for re-treatment at a lower dose.
Part 2: Dose Expansion Once the maximum tolerated dose has been established or determined, 4-10 additional patients will be treated at the maximum tolerated dose of lenalidomide and ibrutinib at the same schedule as above. Dexamethasone will be given at the same dose as in the dose escalation portion of the study.
Patients who discontinue treatment for protocol defined reasons will go to survival follow-up. Once a patient has entered the survival follow-up phase of the trial, his/her therapy is at the discretion of the treating physician. Patients' charts will be reviewed for progression and survival endpoints during visits with treating physicians.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Men and women ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Appendix I).
Symptomatic multiple myeloma (MM) (as defined by revised IMWG criteria) with measurable disease, defined here as having at least one of the following:
At least 1 prior therapy with demonstrated disease progression following the most recent line of treatment.
Progression of disease within 60 days of completion of last therapeutic regimen or the failure to achieve minimal response while on last treatment (according to IMWG).
• Patients should not have progressed on lenalidomide at a dose of more than 10mg
No prior treatment with ibrutinib or any other protein kinase inhibitory drug or drug targeting the b-cell receptor (BCR) signal transduction pathway.
Patients with prior daratumumab and allogeneic stem cell transplant are included.
PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN, except if on anticoagulation for medical reasons in which case INR should be ≤ 3
Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to registration, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screen and enrollment defined as:
Biochemical values must be within the following limits within 7 days prior to registration
Ability to understand and willingness to sign a written informed consent form (ICF).
Ability to adhere with the study visit schedule and other protocol procedures.
A negative pregnancy test will be required for all women of child bearing potential within 7 days prior to registration. Breast feeding is not permitted.
Fertility requirements
Willingness to provide blood and tissue samples for correlative research purposes
Exclusion criteria
Prior history of: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, osteosclerotic myeloma, Crow-Fukase syndrome, primary amyloidosis or plasma cell leukemia.
Radiotherapy within 21 days of registration. However, if the radiation portal was localized to single lesion or fracture site and covered by ≤ 5% of the bone marrow reserve (by investigator estimate), the subject may be enrolled irrespective of the end date of radiotherapy.
Prior chemotherapy:
No concomitant high dose corticosteroids (concurrent use of corticosteroids). EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc.
Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration or baseline QTcF of > 470.
Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction.
History of prior malignancy, with the exception of the following:
Peripheral neuropathy Grade > 2 on clinical examination within 14 days prior to registration.
Uncontrolled diabetes mellitus.
Currently active systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
Use of antibiotics for treatment of infection within 14 days prior to registration
Recent infection requiring systemic treatment that was completed within 14 days of registration.
Known infection with human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.
Note: Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result within 14 days prior to registration.
History of stroke or intracranial hemorrhage within 6 months prior to registration.
Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or patient who requires continuous treatment with a strong CYP3A inhibitor (Appendix II).
Currently active, clinically significant hepatic impairment (Child-Pugh class B or C) according to the Child Pugh classification (Appendix III).
Lactating or pregnant
Major surgery within 4 weeks prior to registration
Known bleeding disorders (e.g. von Willebrand's disease or hemophilia).
Allergies and adverse drug reactions: history of allergy to study drug components
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
Any life-threatening illness, medical condition, or organ systemic dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
Unresolved toxicities from prior anti-cancer therapy, defined as not having resolved to CTCAE Version 5.0, Grade 0 or 1, with the exception of alopecia.
Primary purpose
Allocation
Interventional model
Masking
14 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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