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

Phase 1

Completed

• Conditions: Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm
• Interventions: Drug: RAD001; Drug: Sorafenib

• Registration Number: NCT00474929
• Lead Sponsor: Mayo Clinic

Brief Summary

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.

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 Timeline

• Study First Submitted: 2007-05-16
• Study First Submitted QC: 2007-05-16
• Study First Posted: 2007-05-17
• Study Start: 2007-08-29
• Primary Completion: 2011-11-05
• Results First Submitted: 2015-03-23
• Results First Submitted QC: 2016-05-26
• Results First Posted: 2016-07-07
• Status Verified: 2019-02
• Study Completion: 2019-08-08
• Last Update Submitted: 2019-08-09
• Last Update Posted: 2019-08-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 103

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Multiple Myeloma	RAD001	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;
Multiple Myeloma	Sorafenib	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;
Lymphoma	RAD001	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;
Lymphoma	Sorafenib	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;

Primary Outcome Measures

Name	Time	Method
Number of Participants Reporting a Dose Limiting Toxicity (DLT)	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.
Proportion of Confirmed Tumor Responses	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.

Secondary Outcome Measures

Name	Time	Method
Survival Time	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.
Progression Free Survival	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.

Trial Locations

Locations (2)

Mayo Clinic Cancer Center; 🇺🇸 Rochester, Minnesota, United States

Holden Comprehensive Cancer Center at University of Iowa; 🇺🇸 Iowa City, Iowa, United States