Sorafenib and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
University of Iowa
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00474929
First received: May 16, 2007
Last updated: May 26, 2016
Last verified: March 2016
  Purpose

RATIONALE: Sorafenib and everolimus may stop the growth of cancer cells by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib and everolimus and to see how well they work in treating patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma.


Condition Intervention Phase
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Drug: RAD001
Drug: Sorafenib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Raf Kinase/VEGFR Inhibitor Sorafenib in Combination With the mTOR Inhibitor RAD001 (Everolimus) in Patients With Relapsed Non-Hodgkin Lymphoma, Hodgkin Lymphoma, or Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Number of Participants Reporting a Dose Limiting Toxicity (DLT) [ Time Frame: First cycle (28 days) of study treatment ] [ Designated as safety issue: Yes ]

    The Maximum Tolerated Dose (MTD) is 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). Dose-limiting toxicity (DLT) is defined as an adverse event attributed (definitely, probably, or possibly) in first cycle to the study treatment and meeting the following criteria:

    • Grade 4 infection
    • Grade 4 ANC or PLT
    • Grade 3 or higher non-hematologic adverse event.

    NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 will be used to assess adverse events. For this endpoint, the number of patients reporting a DLT event are tabulated.


  • Proportion of Confirmed Tumor Responses [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]

    A confirmed response is defined to be a CR or PR noted as the objective status for eligible patients during cycles 1-12.

    Complete Response (CR):

    • Multiple Myeloma (MM): Negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, and normalization of free light chain (FLC) ratio.
    • Lymphoma: Disappearance of all clinical and radiographic evidence of disease, all lymph nodes of normal size (1.5 cm or less), no splenomegaly.

    Partial Response (PR):

    • MM: 50% reduction of serum or urine M-protein or to less than 200mg/day, a 50% reduction in the difference between involved and uninvolved FLC, and 50% reduction in the size of soft tissue plasmacytoma.
    • Lymphoma: 50% or greater reduction in sum of the products of the dimension for nodal masses; no increase in liver, spleen or node size; no new sites of disease; and a 50% decrease in lymphocyte count if followed at baseline.


Secondary Outcome Measures:
  • Survival Time [ Time Frame: Up to 3 years from registration ] [ Designated as safety issue: No ]
    Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

  • Progression Free Survival [ Time Frame: Up to 3 years from registration ] [ Designated as safety issue: No ]
    Progression Free Survival is defined as the time from registration to the earliest date documentation of disease progression or death. The distribution of time to disease progression will be estimated using the method of Kaplan-Meier.


Enrollment: 103
Study Start Date: August 2007
Estimated Study Completion Date: October 2016
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Multiple Myeloma
Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;
Drug: RAD001
Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day;
Other Name: Everolimus
Drug: Sorafenib
Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily;
Other Name: sorafenib tosylate
Experimental: Lymphoma
Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;
Drug: RAD001
Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day;
Other Name: Everolimus
Drug: Sorafenib
Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily;
Other Name: sorafenib tosylate

Detailed Description:

OBJECTIVES:

  • Determine the maximum tolerated dose (MTD) of sorafenib tosylate and everolimus in patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma.
  • Determine the toxicity of this regimen in these patients.
  • Evaluate the therapeutic activity of this regimen in these patients.
  • Evaluate the pharmacokinetic interaction of this regimen.
  • Correlate clinical (toxicity and/or tumor response or activity) effects with pharmacologic (pharmacokinetic/pharmacodynamic) parameters and/or biologic (correlative laboratory) results.

OUTLINE: This is a multicenter, dose-escalation, phase I study followed by a phase II study.

  • Phase I (closed to accrual as of 2/10/2009): Patients receive oral sorafenib tosylate and oral everolimus on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of sorafenib tosylate and everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 out of at most 6 patients experience a Dose Limiting Toxicity (DLT).

  • Phase II: Patients receive oral sorafenib tosylate twice daily and oral everolimus once daily at the MTD determined in phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow are collected periodically during the study and analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Patients enrolled in phase I also undergo blood sample collection on days 8 and 15 during course 1 and on day 1 of each subsequent course for pharmacokinetic studies.

After completion of study treatment, patients are followed every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 103 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years to 120 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed diagnosis of 1 of the following:

    • Multiple myeloma
    • Non-Hodgkin's lymphoma
    • Hodgkin's lymphoma
  • Relapsed or refractory disease
  • Measurable disease, as defined according to diagnosis as follows:

    • Multiple myeloma, meeting 1 of the following criteria:

      • Serum monoclonal protein ≥ 1.0 g/dL
      • Urine monoclonal protein ≥ 200 mg by 24-hour electrophoresis
      • Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
      • Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease)
    • Lymphoma, meeting 1 of the following criteria:

      • Measurable disease by CT scan or MRI or PET/CT scan, defined as ≥ 1 lesion that has a single diameter of ≥ 2 cm OR tumor cells in the blood ≥ 5 x10^9/L

        • Skin lesions can be used if the area is ≥ 2 cm in ≥ 1 diameter and photographed with a ruler
    • Lymphoplasmacytic lymphoma without measurable lymphadenopathy, meeting both of the following criteria:

      • Bone marrow lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy
      • Quantitative IgM monoclonal protein > 1,000 mg/dL
  • Not a candidate for known standard potentially curative therapy

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Life expectancy ≥ 12 weeks
  • ANC ≥ 1,500/mm³
  • Hemoglobin ≥ 9 g/dL
  • Platelet count ≥ 75,000/mm³
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal
  • AST ≤ 3 times ULN (5 times ULN if liver involvement)
  • Creatinine ≤ 2.5 times ULN
  • INR < 1.5 or activated PTT < 1.5 times ULN (no concurrent anticoagulants)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective barrier contraception during and for at least 2 weeks after completion of study treatment
  • No uncontrolled infection
  • No NYHA class III-IV congestive heart failure
  • No unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months)
  • No myocardial infarction within the past 6 months
  • No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management
  • No known HIV positivity
  • No other active malignancy requiring treatment
  • No inability to swallow
  • No gastrointestinal (GI) function impairment or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection) or preclude use of oral medications
  • No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months
  • No pulmonary hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks
  • No severe or uncontrolled medical conditions or other conditions that would preclude study compliance
  • No liver disease, such as cirrhosis, chronic hepatitis or chronic persistent hepatitis, or uncontrolled infections
  • No serious nonhealing wound, ulcer, or bone fracture
  • No evidence or history of serious bleeding diathesis or coagulopathy, such as hemophilia or von Willebrand's disease
  • No significant traumatic injury within the past 4 weeks
  • No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus)

PRIOR CONCURRENT THERAPY:

  • More than 3 weeks since prior myelosuppressive chemotherapy or biological therapy and recovered
  • More than 4 weeks since prior major surgery or open biopsy

    • Lymph node biopsy within past 4 weeks allowed
  • Prior everolimus allowed
  • No concurrent immunosuppressant therapy

    • Concurrent stable chronic doses of steroids (≤ 20 mg of prednisone per day) for disorders other than lymphoma (i.e., rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, asthma) or for pruritus or fever associated with lymphoma allowed
    • Concurrent corticosteroids at the lowest possible dose necessary to control symptoms in patients with CNS lymphoma allowed
  • No concurrent CYP450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort)
  • No other concurrent immunotherapy, radiotherapy, or chemotherapy
  • No concurrent chronic oxygen therapy
  • No concurrent warfarin or heparin
  • No other concurrent investigational therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00474929

Locations
United States, Iowa
Holden Comprehensive Cancer Center at University of Iowa
Iowa City, Iowa, United States, 52242-1002
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
University of Iowa
Investigators
Principal Investigator: Thomas E. Witzig, MD Mayo Clinic
Principal Investigator: Shaji K. Kumar, MD Mayo Clinic
  More Information

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT00474929     History of Changes
Other Study ID Numbers: LS0689  07-000710  LS0689 
Study First Received: May 16, 2007
Results First Received: March 23, 2015
Last Updated: May 26, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
recurrent adult Hodgkin lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
stage III multiple myeloma
refractory multiple myeloma
Waldenström macroglobulinemia
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
cutaneous B-cell non-Hodgkin lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent adult grade III lymphomatoid granulomatosis

Additional relevant MeSH terms:
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Non-Hodgkin
Plasmacytoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Sorafenib
Everolimus
Sirolimus
Niacinamide
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents

ClinicalTrials.gov processed this record on July 26, 2016