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Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Clinical and Correlative Phase II Study


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Clinical and Correlative Phase II Study


Background:

- Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of
3-4 years.

- Novel agent combinations with proteasome inhibitors demonstrate improved response rates
while increasing survival in MM patients.

- A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy.

- Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased
peripheral neuropathy

Objectives:

- Primary Objectives

--Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and
dexamethasone (CRd) in untreated MM patients

- Secondary Objectives

- Evaluate progression free survival and overall response rate after 8 cycles24 of
CRd combination therapy

- Evaluate duration of response and overall survival of CRd combination therapy

- Evaluate biological activity of carfilzomib and correlate to clinical outcomes

Eligibility:

- Newly diagnosed patients with histologically confirmed multiple myeloma

- Age greater than or equal to 18 years

- Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated
using the Cockcroft- Gault method. If the calculated CrCl based on Cockcroft-Gault
method is < 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The
measured CrCl must also be greater than or equal to 60 ml/min.

- Without serious co-morbidity that would interfere with receipt of CRd

- Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater
than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL

- Adequate hepatic function, with bilirubin less than 1.5 x the ULN, and AST and ALT less
than 3.0 x ULN

Design:

- Single arm, single stage phase II trial of combination therapy (carfilzomib,
lenalidomide, and dexamethasone) for untreated multiple myeloma patients with an early
stopping rule for toxicity

- Patients will receive 8 cycles of induction combination therapy of CRd

- Each cycle consists of 28-days

- After 4 cycles of therapy, transplant eligible patients will undergo stem cell
collection

- Patients achieving stable disease or better after 8 cycles of CRd will receive
lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will
have the option to continue extended dosing (phase II) for one additional year.

- Patients will have routine blood work with SPEP and free light chains monthly

- Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of
diagnosis and correlative studies

- Patients will also undergo evaluation for minimal residual disease at regular interval
time points, using multi-parametric flow cytometry and FDG PET-CT

- A single stage phase II design will be employed, with an early stopping rule. Unless 4
or more patients in the first 20 have Grade 3 or higher neurologic toxicity in the
first 2 completed cycles, a total of 45 evaluable patients will be enrolled in this
study.

Inclusion Criteria


- INCLUSION CRITERIA:

- Newly diagnosed patients with histologically confirmed MM based on the following
criteria:

1. Clonal plasma cells in the bone marrow

2. Measurable disease within the past 4 weeks defined by any one of the following:

1. Serum monoclonal protein greater than or equal to 1.0 g/dL

2. Urine monoclonal protein greater than200 mg/24 hour

3. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal
kappa/lambda ratio

3. Evidence of underlying end organ damage attributed to underlying plasma cell
proliferative disorder meeting at least one of the following:

1. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L

2. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL

3. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal
reference

4. Bone disease: lytic lesions, severe osteopenia or pathological fractures

- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by
Cockcroft-Gault method. CrCl (calculated) = (140 - Age) x Mass (in kilograms) x [0.85
if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on
Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection to
measure CrCl. The measured CrCl msut be also greater than or equal to 60 ml/min.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of carfilzomib in combination with lenalidomide in
patients less than18 years of age, children are excluded from this study, but will be
eligible for future pediatric trials.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater
than or equal to 8 g/dL (transfusions are permissible), and platelet count greater
than or equal to 75 K/uL

- Adequate hepatic function, with bilirubin less than 1.5 times the ULN, and AST and
ALT less than 3.0 times ULN.

- All study participants must be able to tolerate one of the following
thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin
(coumadin).

- All study participants must be registered into the mandatory RevAssist(Registered
Trademark) program, and be willing and able to comply with the requirements of
RevAssist(Registered Trademark).

- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test within 10 - 14 days and again within 24 hours prior to prescribing
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either
commit to continued abstinence from heterosexual intercourse or begin TWO acceptable
methods of birth control, one highly effective method and one additional effective
method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP
must also agree to ongoing pregnancy testing. Men must agree to use a latex condom
during sexual contact with a FCBP even if they have had a successful vasectomy.

- Subjects must be able to give informed consent

EXCLUSION CRITERIA:

- Prior or concurrent systemic treatment for MM.

- Treatment of hypercalcemia or spinal cord compression or aggressively
progressing myeloma with corticosteroids is permitted.

- Bisphosphonates are permitted.

- Treatment with corticosteroids for indications other than MM is permitted.

- Radiotherapy is permitted.

- Treatment for smoldering myeloma is permitted.

- Plasma cell leukemia

- Pregnant or lactating females. Because there is a potential risk for adverse events
in nursing infants secondary to treatment of the mother with carfilzomib in
combination with lenalidomide, breastfeeding should be discontinued if the mother is
treated with carfilzomib and lenalidomide. These potential risks may also apply to
other agents used in this study.

- Uncontrolled hypertension or diabetes

- Active hepatitis B or C infection

- Has significant cardiovascular disease with NYHA Class III or IV symptoms, or
hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction
within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as
determined by history and physical examination. Echocardiogram will be performed if
clinically warranted.

- Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel
disease, or bowel resection that would prevent absorption

- Uncontrolled intercurrent illness including but not limited to active infection or
psychiatric illness/social situations that would compromise compliance with study
requirements

- Significant neuropathy greater than or equal to Grade 3 at baseline

- Contraindication to any concomitant medication, including antivirals, anticoagulation
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

- Major surgery within 1 month prior to enrollment

- Recruitment Strategies:

- Patients that progress from the SMM and MGUS Natural History Study (NCI
Protocol: 10-C-0096) will be potential candidates.

- Other participant sources will be from outside physician referrals.

- Our ongoing natural history study and outside physician referral network has a
high representation of minorities.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and dexamethasone (CRd) in untreated MM patients

Outcome Time Frame:

4 years

Safety Issue:

Yes

Principal Investigator

Carl O Landgren, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110221

NCT ID:

NCT01402284

Start Date:

July 2011

Completion Date:

September 2015

Related Keywords:

  • Multiple Myeloma
  • Novel Drug Combinations
  • Protease Inhibitors
  • Decreased Peripheral Neuropathy
  • Auto Stem Cell Transplant
  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892