Vorinostat (MK-0683, SAHA [Suberoylanilide Hydroxamic Acid]) + Lenalidomide + Dexamethasone in Multiple Myeloma (MM) (MK-0683-074)

Study Overview
=================
Brief Summary
-----------------
The purpose of this Phase I study of vorinostat in combination with lenalidomide and dexamethasone in participants with relapsed or refractory multiple myeloma is to determine the maximum tolerated dose (MTD) as estimated by the incidence of dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D) as estimated by the incidence of drug-related adverse events (AEs).

Official Title
-----------------
A Phase I Study of Vorinostat in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Conditions
-----------------
Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Vorinostat
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is a male or female at least 18 years old Has relapsed or refractory MM and has had at least one prior therapy Female participants of childbearing potential must have 2 negative serum pregnancy tests prior to receiving the first dose of study drugs Female participants who can become pregnant must agree to use 2 separate forms of effective birth control at the same time, 4 weeks before, while taking, and for 4 weeks after stopping lenalidomide; post menopausal participants should be free from menses for >2 years, or are surgically sterilized Male participant agrees to use an adequate method of contraception for the duration of the study, even if the participant has undergone a successful vasectomy Male participants must agree to use a latex condom during sexual contact with a pregnant female or a female who can become pregnant; this is required for the duration of the study, and for 4 weeks after stopping therapy Has at least 3 weeks washout prior to treatment Is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis Exclusion Criteria: Has prior treatment with a histone deacetylase (HDAC) inhibitor Has prior allogenetic bone marrow transplant Has received intravenous antibiotics, antiviral, or antifungal agents within 2 weeks prior to the start of the study drug Uses illicit drugs, substance abuse or had a recent history (within the last year) of drug or alcohol abuse Is pregnant or breast feeding or expecting to have a baby during the course of the study Has human immunodeficiency virus (HIV) infection Has Hepatitis B/C infection Is currently receiving treatment for another type of cancer other than skin or cervical cancer that has not been in remission for 5 years or longer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Level 1: Vorinostat 300 mg + lenalidomide 10 mg<br>Participants will receive vorinostat 300 mg orally once-daily (QD) on Days 1-7 and Days 15-21; lenalidomide 10 mg orally QD on Days 1-21 and dexamethasone 40 mg orally QD on Days 1, 8, 15 and 22 of each 28-day cycle for up to 8 cycles. Qualified participants who don't have disease progression can continue treatment after 8 cycles at the same dose and schedule, until progressive disease or unacceptable toxicity. | Drug: Vorinostat<br>* Vorinostat 300 mg or 400 mg QD via oral capsule on Days 1-7 and Days 15-21 of each 28-day cycle.<br>* Other names: Zolinza;Drug: Lenalidomide<br>* Lenalidomide 10 mg, 15 mg, 20 mg or 25 mg QD via oral capsule on Days 1-21 of each 28-day cycle.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Dexamethasone 40 mg QD via oral tablet on Days 1, 8, 15 and 22 of each 28-day cycle.<br>* Other names: Decadron;|
| Experimental: Level 2: Vorinostat 400 mg + lenalidomide 10 mg<br>Participants will receive vorinostat 400 mg orally QD on Days 1-7 and Days 15-21; lenalidomide 10 mg orally QD on Days 1-21 and dexamethasone 40 mg orally QD on Days 1, 8, 15 and 22 of each 28-day cycle for up to 8 cycles. Qualified participants who don't have disease progression can continue treatment after 8 cycles at the same dose and schedule, until progressive disease or unacceptable toxicity. | Drug: Vorinostat<br>* Vorinostat 300 mg or 400 mg QD via oral capsule on Days 1-7 and Days 15-21 of each 28-day cycle.<br>* Other names: Zolinza;Drug: Lenalidomide<br>* Lenalidomide 10 mg, 15 mg, 20 mg or 25 mg QD via oral capsule on Days 1-21 of each 28-day cycle.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Dexamethasone 40 mg QD via oral tablet on Days 1, 8, 15 and 22 of each 28-day cycle.<br>* Other names: Decadron;|
| Experimental: Level 3: Vorinostat 400 mg + lenalidomide 15 mg<br>Participants will receive vorinostat 400 mg orally QD on Days 1-7 and Days 15-21; lenalidomide 15 mg orally QD on Days 1-21 and dexamethasone 40 mg orally QD on Days 1, 8, 15 and 22 of each 28-day cycle for up to 8 cycles. Qualified participants who don't have disease progression can continue treatment after 8 cycles at the same dose and schedule, until progressive disease or unacceptable toxicity. | Drug: Vorinostat<br>* Vorinostat 300 mg or 400 mg QD via oral capsule on Days 1-7 and Days 15-21 of each 28-day cycle.<br>* Other names: Zolinza;Drug: Lenalidomide<br>* Lenalidomide 10 mg, 15 mg, 20 mg or 25 mg QD via oral capsule on Days 1-21 of each 28-day cycle.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Dexamethasone 40 mg QD via oral tablet on Days 1, 8, 15 and 22 of each 28-day cycle.<br>* Other names: Decadron;|
| Experimental: Level 4: Vorinostat 400 mg + lenalidomide 20 mg<br>Participants will receive vorinostat 400 mg orally QD on Days 1-7 and Days 15-21; lenalidomide 20 mg orally QD on Days 1-21 and dexamethasone 40 mg orally QD on Days 1, 8, 15 and 22 of each 28-day cycle for up to 8 cycles. Qualified participants who don't have disease progression can continue treatment after 8 cycles at the same dose and schedule, until progressive disease or unacceptable toxicity. | Drug: Vorinostat<br>* Vorinostat 300 mg or 400 mg QD via oral capsule on Days 1-7 and Days 15-21 of each 28-day cycle.<br>* Other names: Zolinza;Drug: Lenalidomide<br>* Lenalidomide 10 mg, 15 mg, 20 mg or 25 mg QD via oral capsule on Days 1-21 of each 28-day cycle.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Dexamethasone 40 mg QD via oral tablet on Days 1, 8, 15 and 22 of each 28-day cycle.<br>* Other names: Decadron;|
| Experimental: Level 5: Vorinostat 400 mg + lenalidomide 25 mg<br>Participants will receive vorinostat 400 mg orally QD on Days 1-7 and Days 15-21; lenalidomide 25 mg orally QD on Days 1-21 and dexamethasone 40 mg orally QD on Days 1, 8, 15 and 22 of each 28-day cycle for up to 8 cycles. Qualified participants who don't have disease progression can continue treatment after 8 cycles at the same dose and schedule, until progressive disease or unacceptable toxicity. | Drug: Vorinostat<br>* Vorinostat 300 mg or 400 mg QD via oral capsule on Days 1-7 and Days 15-21 of each 28-day cycle.<br>* Other names: Zolinza;Drug: Lenalidomide<br>* Lenalidomide 10 mg, 15 mg, 20 mg or 25 mg QD via oral capsule on Days 1-21 of each 28-day cycle.<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Dexamethasone 40 mg QD via oral tablet on Days 1, 8, 15 and 22 of each 28-day cycle.<br>* Other names: Decadron;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) | DLTs consisted of hematologic or non-hemtologic toxicities. Hematologic DLT was any grade (gr) 4 neutropenia lasting ≥7 days, gr 4 thrombocytopenia or gr 5 hematologic toxicity. Non-hematologic DLT was any gr 3, 4 or 5 non-hematologic toxicity with the exception of (1) gr 3 nausea, vomiting, diarrhea or dehydration not compliant with medical care, lasting <48 hours (2) gr 3 acidosis/alkalosis returning to ≤ gr 2 by 48 hours of medical care (3) gr 3 liver function test elevation without symptoms, lasting ≤5 days (4) Gr 3 amylase elevation without symptoms (5) Gr 3 hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia or hyphosphatemia responding to medical care (6) Gr 3 hypercholeresterolemia or hypertriglyceridemia. A drug-related AE causing dose modification of study drug is also considered a DLT. Per protocol DLTs were analyzed in the first 28-day treatment cycle. The number of participants experiencing DLTs is reported here for all participants who got ≥1 dose of study drug. | Cycle 1 (Up to 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Drug-Related Adverse Events (AEs) | An AE was defined as any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. An AE was considered related to a drug as determined by the investigator based on exposure (evidence of exposure to drug), time course (time of AE onset versus drug-induced effect), likely cause (AE etiology related or un-related to drug), de-challenge (drug dose reduction/discontinuation) or re-challenge (drug re-exposure). Per protocol participants experiencing drug-related AEs were analyzed at the time of the protocol-specified final statistical analysis with a 3-September (Sep)-2012 data cut-off. The number of participants experiencing drug-related AEs is reported here for all participants who got ≥1 dose of study drug. | Up to  55 months (through pre-specified final statistical analysis cut-off date of 3-Sep-2012) |