Primary Objective:• To evaluate the proportion of patients with a response of very good partial response (VGPR) or better to IDd treatment.Secondary Objectives:• To measure progression-free survival (PFS), time to progression (TTP), and overall…
ID
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Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is response of VGPR or better as assessed by the
investigator. Additionally efficacy will be assessed by PFS, TTP, ORR, TTR,
DOR, and OS. Patients will be assessed for disease response by the investigator
according to the IMWG criteria.
Secondary outcome
Safety assessments will be evaluated through the incidence and severity of
adverse events (AEs) and changes in clinical hematology and chemistry
laboratory test results.
Background summary
See protocol (page 17), section 4.1 Background.
Study objective
Primary Objective:
• To evaluate the proportion of patients with a response of very good partial
response (VGPR) or better to IDd treatment.
Secondary Objectives:
• To measure progression-free survival (PFS), time to progression (TTP), and
overall survival (OS).
• To measure overall response rate (ORR), time to response (TTR), and duration
of response (DOR).
• To collect plasma concentration-time data for ixazomib to contribute to
population pharmacokinetic (PK) analyses.
• To evaluate the safety/tolerability of IDd administered in a 28-day cycle.
Study design
This is a prospective, open-label, multicenter study. There will be a screening
period, followed by a treatment period (divided into cycles of 28 days) with
administratino of the combination of ixazomib, daratumumab and dexamethasone to
the patients. All patients will receive study medication until they experience
progressive disease (PD) or have an unacceptable toxicity. After the last dose
of study medication, and end of study visit is done and followed by 2 follow-up
periods: progression free survival (PFS) follow up (if needed) and overall
survival (OS) follow up.
Intervention
For the purposes of this protocol, study treatment regimen is defined as the
combination of ixazomib, daratumumab, and dexamethasone. All cycles are
approximately 28 days with treatment given until PD or unacceptable toxicity.
(Full details on study treatment administration are in Section 8.2.) See
diagram below for details.
• Ixazomib will be administered at 4 mg orally on Days 1, 8, and 15 of each
28-day cycle. In Cycle 1 ixazomib will be given after the daratumumab infusion;
in subsequent cycles, if there have been no Grade 3 or higher
infusion-related reactions (IRRs) in the previous cycle, ixazomib can be given
prior to or at approximately the same time as the premedications (see Section
8.2.3).
• Daratumumab will be administered intravenously (IV) at 16 mg/kg (note pre-
and postinfusion medications of antipyretics and oral antihistamines listed in
Section 8.2.2): Daratumumab will be given on the following schedule:
o Cycles 1 and 2: Days 1, 8, 15, and 22 (every week; total of 8 doses).
o Cycles 3 to 6: Days 1 and 15 (every 2 weeks; total of 8 doses).
o Cycles 7 and beyond: Day 1 (every 4 weeks).
• Dexamethasone will be given as 20 mg on Day 1, 2, 8, 9, 15, 16, 22, and 23 in
each 28-day cycle, to achieve the standard total of 40 mg per week (2 doses of
20 mg per week). This schedule allows for dexamethasone to be given the day of
(before) and the day after the daratumumab infusion on daratumumab dosing days.
Dexamethasone should be given IV before the first daratumumab dose; but can be
given IV or orally thereafter. The dose of dexamethasone may be reduced in some
patients (see details in Section 8.2.4).
Study burden and risks
Potential discomforts and risks of ixazomib
Based on studies of ixazomib it is possible to predict some of the discomforts
and risks. However, it is possible that ixazomib may cause risks that have not
yet been observed in patients. The following risks might be seen:
• Low platelet count which may increase the chance of bleeding
• Skin rash which may range from some red areas, small flat spots, or small
raised bumps that may or may not be itchy in a few areas or all over the body
• Feeling tired or weak
• Nausea
• Vomiting
• Diarrhea
• Numbness, tingling or pain feelings in hands and feet
• Constipation
• Lowered red blood cells or anemia which may make you feel tired
• Lowered white blood cells called neutrophils that may increase your risk of
infection and may be associated with fever
More information on possible discomforts and risks of ixazomib and of the study
procedures can be found in Appendix F of the ICF.
Potential discomforts and risks of daratumumab
Based on previous studies of daratumumab, it is possible to predict some of the
discomforts and risks associated with this drug. However, it is possible that
daratumumab in combination with ixazomib may cause risks that have not yet been
observed in patients. Daratumumab has not been studied in combination with
ixazomib, however the following risks have been seen in association with
daratumumab treatment when it is given alone and not in combination with any
other medications, according to the prescribing information of the marketed
product Darzalex:
• Infusion reactions that can be severe and can cause symptoms such as
narrowing of the airways, low oxygen, shortness of breath, high blood pressure,
swelling in the throat and fluid in the lungs, nasal congestion, cough, throat
irritation, chills, vomiting, or nausea. Less common symptoms were wheezing,
runny nose, fevers, chest discomfort, itching and low blood pressure.
Approximately half of all patients experienced a reaction, most during the
first infusion. Infusion reactins can also occur with subsequent infusions.
Nearly all reactions occurred during infusion or within 4 hours of completing
daratumumab.
• Fatigue
• Fever
• Chills
• Cough
• Nasal congestion
• Shortness of breath
• Back pain
• Joint pain
• Pain in arms and legs
• Pain in the chest that is muscular pain
• Upper respiratory tract infection
• Pneumonia
• Inflammation of the nose or throat (nasopharyngitis)
• Nausea
• Diarrhea
• Constipation
• Vomiting
• Decreased appetite
• Headache
• High blood pressure
• Low levels of red blood cells
• Low levels of platelets
• Low levels of white blood cells (lymphopenia)
• Low neutrophils, a type of white blood cell (neutropenia)
More information on possible discomforts and risks of daratumumab can be found
in Appendix F of the ICF.
Potential discomforts and risks of dexamethasone
Dexamethasone is a corticosteroid medication that can be associated with the
following more common risks:
• Dermatologic: acne, allergic skin inflammation, dry scaly skin, easy
bruising, redness of the skin, impaired wound healing, increased sweating,
rash, stretching and thinning of the skin, thinning scalp hair, hives
• Metabolism: decreased sugar tolerance, high blood sugar, sugar in the urine,
body hair growth, worsening of diabetes in patients who already have diabetes,
irregular menstrual cycles, increased breakdown of protein
• Fluid and electrolyte changes: fluid retention, low potassium in the blood,
potassium loss, sodium retention
• Gastrointestinal: increased appetite, nausea, peptic ulcer, ulcerations in
the esophagus
• Musculoskeletal: damage to the head of the femur or humurus bones (long bones
in the leg or arm, respectively), loss of muscle mass, muscle weakness,
osteoporosis
• Neurological/Psychiatric: depression, emotional instability, headache,
increased pressure inside the skull, insomnia, mood swings, psychic disorders,
• Ophthalmic: increased pressure inside the eye, cataracts, glaucoma
• Other: Abnormal fat deposits, decreased resistance to infection, hiccups,
moon face, weight gain
More information on possible discomforts and risks of dexamethasone can be
found in Appendix F of the ICF.
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Listed location countries
Age
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled
in the study:
• Adult patients (aged >=18 years) who have been diagnosed with MM according to
IMWG criteria.
• All patients must have measurable disease by at least 1 of the following
measurements:
- Serum M-protein >=1 g/dL (>=10 g/L).
- Urine M-protein >=200 mg/24 hours.
• All patients must have documented evidence of PD on or after their last
regimen as defined by IMWG criteria (see Appendix E) [1-3]. All patients must
have received between 1 to 3 prior therapies for MM (a prior therapy is defined
as 2 or more cycles of therapy given as a treatment plan for MM [eg, a
single-agent or combination therapy or a sequence of planned treatments such as
induction therapy followed by autologous SCT and then consolidation and/or
maintenance therapy]).
• All patients must have achieved a response (PR or better) to at least 1 prior
therapy.
• All patients must have an Eastern Cooperative Oncology Group (ECOG) score of
0, 1, or 2.
• All patients must meet the following laboratory criteria:
- Absolute neutrophil count (ANC) >=1000/mm3.
- Platelet count >=75,000/mm3.
- Total bilirubin <=1.5 x the upper limit of the normal range (ULN) (except for
Gilbert syndrome: direct bilirubin <=2 x ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 x ULN.
- Calculated creatinine clearance >=50 mL/min.
• Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to use effective contraceptive
measures during and for 90 days following treatment. Advise women using
hormonal contraceptives to also use a barrier method of contraception (see
Appendix H for details).
• Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to use effective contraceptive measures during and for 90 days
following treatment (see Appendix H for details).
• Voluntary written consent must be given before performance of any
study-related procedure not part of standard medical care, with the
understanding that consent may be withdrawn by the patient at any time without
prejudice to future medical care.
• Patient is willing and able to adhere to the study visit schedule and other
protocol requirements.
Exclusion criteria
Patients meeting any of the following exclusion criteria are not to be enrolled
in the study:
• Patients have undergone prior allogenic bone marrow transplantation.
• Patients have received prior ixazomib at any time or daratumumab or other
anti-CD38 therapies, except as part of initial therapy if this was stopped to
move on to SCT and the patient did not progress on anti-CD38 treatment.
• Patients are refractory to bortezomib or carfilzomib at the last exposure
before this study (defined as patient having PD while receiving bortezomib or
carfilzomib therapy or within 60 days after ending bortezomib or carfilzomib
therapy).
• Patients planning to undergo SCT prior to PD on this study (ie, these
patients should not be enrolled in order to reduce disease burden prior to
transplant).
• Patients receiving systemic treatment with strong CYP3A inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, St. John's
wort) within 14 days before randomization.
• Patient has received autologous SCT within 12 weeks before the date of study
treatment.
• Patient has received an investigational drug (including investigational
vaccines) within 4 weeks before study treatment (except for investigational
antimyeloma agents, which cannot be taken within 2 weeks prior or 5 PK
half-lives of the treatment, whichever is longer, before the date of study
treatment). The only exception is emergency use of a short course of
corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum 4 days)
before treatment.
• Patients with known chronic obstructive pulmonary disease (COPD) with a
forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note:
FEV1 testing is required for subjects suspected of having COPD and subjects
must be excluded if FEV1 is <50% of predicted normal.
- Patients with Grade 2 or higher residual toxicities from prior therapy
(including Grade 2 or higher peripheral neuropathy or any grade neuropathy with
pain; excluding alopecia). This includes recovery from any major surgery. Note:
Subjects with planned surgical procedures to be conducted under local
anesthesia may participate. Kyphoplasty or vertebroplasty are not considered
major surgery.
• Patients with known allergy to any of the study medications, their analogues,
their excipients, mAbs or human proteins or known sensitivity to
mammalian-derived products.
• Patient has uncontrolled clinically significant cardiac disease, including
myocardial infarction within 6 months before date of study entry or unstable or
uncontrolled angina, congestive heart failure, New York Heart Association
(NYHA) Class III-IV, uncontrolled cardiac arrhythmia (Grade 2 or higher).
• Patients with ongoing or active systemic infection requiring IV medical
management; patients with known HIV-RNA positivity; patients with hepatitis B
virus (HBV) surface antigen or core antibody positivity,; and patients with
known hepatitis C virus-RNA positivity. Patients who have positive hepatitis C
antibody can be enrolled but must have hepatitis C virus-RNA negativity.
• Patient has any concurrent medical condition or disease that is likely to
interfere with study procedures, results, or assessment of safety or toxicity
or that in the opinion of the investigator would constitute a hazard for
participating in this study.
• Patients 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 nonmelanoma skin cancer or
carcinoma in situ of any type are not excluded if they have undergone complete
resection.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003977-32-NL |
| ClinicalTrials.gov | NCT03439293 |
| CCMO | NL65162.029.18 |