Carfilzomib and Melphalan Before Stem Cell Transplant in Treating Patients With Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects and best dose of carfilzomib when given together with melphalan and to see how well they work in treating patients with multiple myeloma before stem cell transplant. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving carfilzomib together with melphalan may kill more cancer cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of carfilzomib that can be added to high dose melphalan as part of conditioning chemotherapy for myeloma. (Phase I) II. To determine the efficacy of the combination in patients with myeloma undergoing stem cell transplantation, as defined by achievement of complete response (CR). (Phase II) SECONDARY OBJECTIVES: I. To examine the toxicities associated with addition of carfilzomib to high dose melphalan in patients with multiple myeloma (MM). II. To determine the progression free rate at 1 and 2 years post registration. TERTIARY OBJECTIVES: I. To determine the proportion of patients achieving a minimal residual disease (MRD) negative status. II. To assess the HevyLite assay prior to and during treatment. OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II study. CONDITIONING: Patients receive carfilzomib intravenously (IV) over 30 minutes on days -6, -5, -2, and -1. Patients also receive melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. After completion of study treatment, patients are followed up at day 30, day 100, and then every 90 days for up to 5 years.

Official Title
-----------------
A Phase 1/2 Trial of Carfilzomib and Melphalan and Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma (CARAMEL)

Conditions
-----------------
DS Stage I Plasma Cell Myeloma, DS Stage II Plasma Cell Myeloma, DS Stage III Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

Intervention / Treatment
-----------------
* Procedure: Autologous Bone Marrow Transplantation
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carfilzomib
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Serum creatinine =< 2 mg/dL Absolute neutrophil count >= 1000/uL Platelet count >= 50,000/uL Hemoglobin >= 8.0 g/dL Diagnosis of symptomatic MM Measurable disease of multiple myeloma at the time of baseline values for disease assessment 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 Bone marrow plasma cells >= 30% NOTE: For patients with no relapse prior to transplant, measurable disease at the time of diagnosis NOTE: For patients who have had a disease relapse prior to transplant, measurable disease at the time of the most recent relapse immediately prior to transplant; NOTE: If the patient had treatment for the relapsed disease prior to transplant, the patient must have measurable disease at the time of relapse prior to this therapy Patient is considered for autologous stem cell transplantation with full dose melphalan (200 mg/m^2) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity) Provide informed written consent Ejection fraction >= 45% Corrected pulmonary diffusion capacity of greater than or equal to 50% Forced expiratory volume in 1 second (FEV1) >= 50% Forced vital capacity (FVC) >= 50% Negative pregnancy test performed =< 7 days prior to registration, for women of childbearing potential only Willing to return to Mayo Clinic Rochester, Mayo Clinic Arizona, Mayo Clinic Florida for treatment Note: During the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up Willing to provide blood and bone marrow samples for correlative research purposes Exclusion Criteria: Prior autologous or allogeneic bone marrow/peripheral blood stem cell transplant More than two prior regimens for therapy of MM Myocardial infarction within 6 months prior to enrollment, or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; NOTE: Prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant Seroreactivity for human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV) I or II, hepatitis B virus (HBV), hepatitis C virus (HCV) Other active malignancy < 2 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer Any of the following: Pregnant women or women of reproductive capability who are unwilling to use effective contraception Nursing women Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 28 days after stopping treatment Other co-morbidity, which would interfere with patient's ability to participate in the trial, e.g. uncontrolled infection, uncompensated lung disease Concurrent chemotherapy, radiotherapy, 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 Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>CONDITIONING: Patients receive carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. | Procedure: Autologous Bone Marrow Transplantation<br>* Undergo autologous stem cell transplant<br>* Other names: Autologous Marrow Transplantation;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous stem cell transplant<br>* Other names: Autologous Stem Cell Transplantation;Drug: Carfilzomib<br>* Given IV<br>* Other names: PR-171;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose by the Number of Patients With a DLT Per Dose Level | Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity(DLT) in at least one-third of patients. For this study, a DLT is any of the following during the first 2 cycles of treatment; Absolute neutrophil count engraftment* delayed beyond day 21 or Platelet engraftment* delayed beyond day 30, grade 3+ related sensory or motor neuropathy, or grade 4+ related non-neurologic or non-hematologic adverse event(excluding nausea, vomiting, and diarrhea. Reported below are the number of patients who experienced a DLT. | Up to day 30 | 
| Percentage of Patients With Complete Responses, Defined as a Complete Response Noted as the Objective Status on Two Consecutive Evaluations (Phase II) | The percentage of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success percentages will be calculated. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event Rate, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | These results are reported in the adverse events section. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. | Up to 5 years | 
| Complete Response Rate at Day 100 | Complete response rate (CRR) is defined as the percentage of complete responses estimated by the total number of patients who achieve a complete response by day 100 post-transplant divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true complete response rate at day 100 will be calculated. | At day 100 | 
| Progression Free Percentage at 1 and 2 Years Post Registration | Progression is an Increase of 25% from lowest value in any of the following (A 25% increase refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft tissue plasmacytoma or hypercalcemia. The lowest value does not need to be a confirmed value. If the lowest serum Mprotein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression.), (In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), that value will not be considered when determining the lowest value.): Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) and/or If the only measurable disease is FLC, the difference between involved and uninvolved FLC levels (absolute increase must be>10 mg/dL) and/or If the only measurable disease is BM, bone marrow PC percentage (absolute increase must be ≥ 10%) (Bone marrow criteria for PD | At 1 year and 2 years |