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Phase 1/2 Trial of MLN9708 in Combination With Cyclophosphamide and Dexamethasone in Patients With Previously Untreated Symptomatic Multiple Myeloma


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

Phase 1/2 Trial of MLN9708 in Combination With Cyclophosphamide and Dexamethasone in Patients With Previously Untreated Symptomatic Multiple Myeloma


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of cyclophosphamide that can be combined with
MLN9708 (ixazomib) and dexamethasone in patient with previously untreated symptomatic
multiple myeloma (MM). (Phase I) II. To determine the complete plus very good partial
response rate (>= VGPR) of MLN9708, used in combination with cyclophosphamide and
dexamethasone in patients with previously untreated symptomatic MM. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival and overall survival among patients with
previously untreated symptomatic MM following treatment with MLN9708 in combination with
cyclophosphamide and dexamethasone followed by MLN9708 maintenance till progression.

II. To determine the toxicities associated with MLN9708 in combination with cyclophosphamide
and dexamethasone in patients with previously untreated symptomatic MM.

TERTIARY OBJECTIVES:

I. To examine the pharmacokinetics of MLN9708 when used in combination with cyclophosphamide
and dexamethasone.

II. To assess the incidence of neurotoxicity using patient completed questionnaires.

OUTLINE: This is a phase 1, dose-escalation study of cyclophosphamide followed by a phase II
study.

INDUCTION THERAPY: Patients receive ixazomib orally (PO) on days 1, 8, and 15 and
cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every
28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ixazomib PO on days 1, 8, and 15. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.


Inclusion Criteria:



- Calculated creatinine clearance (using Cockcroft-Gault equation below) >= 30 mL/min

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 75000/mm^3

- Hemoglobin >= 8.0 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

- Prior therapy for the treatment of solitary plasmacytoma is permitted, but > 14 days
should have elapsed from the last day of radiation; NOTE: prior therapy with
clarithromycin, dehydroepiandrosterone (DHEA), anakinra, pamidronate or zoledronic
acid is permitted; any additional agents not listed must be approved by the principal
investigator

- Measurable disease of multiple myeloma as defined by at least ONE of the following:

- Serum monoclonal protein >= 1.0 g/dL

- > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio

- Previously untreated

- Provide informed written consent

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Willing to follow strict birth control measures as suggested by the study

- Female patients: if they are of childbearing potential, agree to one of the
following:

- Practice 2 effective methods of contraception, at the same time, from the
time of signing the informed consent form through 90 days after the last
dose of study drug, AND must also adhere to the guidelines of any
treatment-specific pregnancy prevention program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject; (periodic abstinence [eg, calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)

- Male patients: even if surgically sterilized (ie, status post-vasectomy), must
agree to one of the following:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject. (periodic abstinence [eg, calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)

- Willing to return to return to enrolling institution for follow-up (during the active
monitoring phase of the study)

Exclusion Criteria:

- Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma

- Prior cytotoxic chemotherapy or corticosteroids for the treatment of multiple
myeloma; NOTE: prior corticosteroid use for the treatment of non-malignant disorders
is permitted

- Diagnosed or treated for another malignancy =< 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease; NOTE: patients with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Other co-morbidity which would interfere with patient's ability to participate in
trial, e.g. uncontrolled infection, uncompensated heart or lung disease

- Other concurrent chemotherapy, or any ancillary therapy considered investigational;
NOTE: bisphosphonates are considered to be supportive care rather than therapy, and
are thus allowed while on protocol treatment

- Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain during
the screening period

- Major surgery =<14 days prior to study registration

- Systemic treatment with strong inhibitors of cytochrome P450 1A2 (CYP1A2)
(fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450 3A4
(CYP3A4) (clarithromycin, conivaptan, telithromycin, itraconazole, voriconazole,
ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St.
John's wort) =< 14 days prior to registration

- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, congestive heart failure, unstable
angina, or myocardial infarction within the past 6 months; Note: prior to study
entry, any electrocardiogram (ECG) abnormality at screening must be documented by the
investigator as not medically relevant

- Radiotherapy =< 14 days prior to registration; NOTE: if the involved field is small,
7 days will be considered a sufficient interval between treatment and administration
of the MLN9708

- Known human immunodeficiency virus (HIV) positive

- Known hepatitis B surface antigen-positive status, or known or suspected active
hepatitis C infection

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol

- Known allergy to any of the study medications, their analogues or excipients in the
various formulations

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the
oral absorption or tolerance of MLN9708 including difficulty swallowing

- Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology
Criteria (CTCAE) grading, in the absence of antidiarrheals

- Participation in clinical trials with other investigational agents not included in
this trial, =< 21days prior to registration on this trial and throughout the duration
of this trial

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally-tolerated dose (MTD) defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients) as assessed by NCI CTCAE version 4.0 (Phase I)

Outcome Time Frame:

Up to 28 days

Safety Issue:

Yes

Principal Investigator

Shaji Kumar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Institutional Review Board

Study ID:

MC1382

NCT ID:

NCT01864018

Start Date:

July 2013

Completion Date:

Related Keywords:

  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Mayo ClinicRochester, Minnesota  55905