Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Formulation of IXAZOMIB (MLN9708), Administered Twice-weekly in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) in phase 1 and to determine the combined response rate of clinical response CR and very good partial response (VGPR) in phase 2 of oral (PO) ixazomib administered twice-weekly in combination with lenalidomide and low-dose dexamethasone in a 21-day cycle in participants with newly diagnosed multiple myeloma (NDDM).

The drug being tested in this study is called ixazomib. Ixazomib was tested to slow disease progression and improve overall survival in participants who have newly diagnosed multiple myeloma (NDMM). This study looked at the safety, tolerability and response in participants when administered in combination with lenalidomide and low-dose dexamethasone.

The study enrolled 64 patients. Participants were assigned to one of the 3 treatment groups:

• Phase 1 Ixazomib 3 mg
• Phase 1 Ixazomib 3.7 mg
• Phase 2 Ixazomib 3 mg

All participants were administered with Ixazomib capsules, orally, twice-weekly on Days 1, 4, 8, and 11 along with lenalidomide capsules, orally, once daily on Days 1-14 and dexamethasone, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib capsules, orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity.

This multi-center trial conducted in the United States. The overall time to participate in this study was 2037 days. Participants will make multiple visits to the clinic, and a final visit after 30 days after last dose of study drug for a follow-up assessment.

Inclusion Criteria:

• Male or female patients 18 years or older
• Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
• Measurable disease as specified in study protocol
• Hematologic, liver, and renal function as specified in the study protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse AND must adhere to the guidelines of the lenalidomide pregnancy prevention program
• Must be able to take concurrent aspirin 325 mg daily
• Voluntary written consent

Exclusion Criteria

• Peripheral neuropathy that is greater or equal to Grade 2
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before the first dose of study drug
• Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug
• Diarrhea (> Grade 1)
• Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)
• Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment
• Central nervous system involvement
• Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Evidence of current uncontrolled cardiovascular conditions
• Prior or concurrent deep vein thrombosis or pulmonary embolism
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
• Known allergy to any of the study medications
• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption, or tolerance of IXAZOMIB
• Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ