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

August 9, 2019 updated by: Mayo Clinic

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

103

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Iowa
      • Iowa City, Iowa, United States, 52242-1002
        • Holden Comprehensive Cancer Center at University of Iowa
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • sorafenib tosylate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Reporting a Dose Limiting Toxicity (DLT)
Time Frame: First cycle (28 days) of study treatment

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.
First cycle (28 days) of study treatment
Proportion of Confirmed Tumor Responses
Time Frame: Up to 12 cycles of treatment

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.
Up to 12 cycles of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival Time
Time Frame: Up to 3 years from registration
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.
Up to 3 years from registration
Progression Free Survival
Time Frame: Up to 3 years from registration
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.
Up to 3 years from registration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Collaborators

University of Iowa

Investigators

  • Principal Investigator: Thomas E. Witzig, MD, Mayo Clinic
  • Principal Investigator: Shaji K. Kumar, MD, Mayo Clinic

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 29, 2007

Primary Completion (Actual)

November 5, 2011

Study Completion (Actual)

August 8, 2019

Study Registration Dates

First Submitted

May 16, 2007

First Submitted That Met QC Criteria

May 16, 2007

First Posted (Estimate)

May 17, 2007

Study Record Updates

Last Update Posted (Actual)

August 20, 2019

Last Update Submitted That Met QC Criteria

August 9, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LS0689 (Other Identifier: Mayo Clinic Cancer Center ID)
  • 07-000710 (Other Identifier: Mayo Clinic IRB)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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