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A Phase I Study of the Raf Kinase/VEGFR Inhibitor BAY 43-9006 in Combination With the Proteasome Inhibitor PS-341 in Patients With Advanced Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Refractory Chronic Lymphocytic Leukemia, Refractory Multiple Myeloma, Stage III Multiple Myeloma, Stage IV Chronic Lymphocytic Leukemia, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of the Raf Kinase/VEGFR Inhibitor BAY 43-9006 in Combination With the Proteasome Inhibitor PS-341 in Patients With Advanced Malignancies


OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of sorafenib and bortezomib in patients
with advanced malignancies.

II. To describe the toxicities associated with the combination of sorafenib and bortezomib.

III. To evaluate the therapeutic antitumor activity of the combination of sorafenib and
bortezomib.

IV. To evaluate the effects of sorafenib on the disposition of bortezomib.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups according
to disease type.

GROUP I (solid tumors-dose-escalation group): Patients receive oral sorafenib twice daily
on days 1-21 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6
patients receive escalating doses of sorafenib and bortezomib until the MTD is determined.
The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience
dose-limiting toxicity.

GROUP II (multiple myeloma or chronic lymphocytic leukemia-maximum tolerated dose [MTD]
group): Patients receive oral sorafenib at the MTD twice daily on days 3-21 of course 1 and
on days 1-21 of each subsequent course. Patients also receive bortezomib IV over 3-5 seconds
at the MTD on days 1, 4, 8, and 11.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 3 months.


Inclusion Criteria:



- Diagnosis of 1 of the following:

- Cytologically or histologically proven unresectable solid tumor for which no
curative treatment options exist (group I - dose-escalation phase)

- Multiple myeloma or chronic lymphocytic leukemia requiring treatment (group II -
maximum tolerated dose phase)

- Failed ≥ 1 prior regimen

- Non-secretory myeloma allowed

- No known standard therapy that is potentially curative or definitely capable of
extending life expectancy exists

- Tumor amenable to serial sampling (group II)

- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,500/mm^3

- Hemoglobin ≥ 9 g/dL

- Platelet count ≥ 100,000/mm^3 (75,000/mm^3 for patients with multiple myeloma [group
II])

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 3 times ULN (5 times ULN if liver involvement)

- Creatinine ≤ 1.5 times ULN (2.5 times ULN for patients with multiple myeloma [group
II])

- Life expectancy ≥ 12 weeks

- No uncontrolled infection

- No New York Heart Association class III or IV heart disease

- No uncontrolled hypertension, labile hypertension, or history of poor compliance with
antihypertensive medication

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No sensory peripheral neuropathy of any etiology > grade 1 or neuropathic pain of any
etiology

- No active HIV infection requiring therapy

- No inability to swallow that would preclude use of oral medications

- No evidence of bleeding diathesis

- Medically capable and willing to provide biologic specimens as required (mandatory
for patients in group II)

- Priorbortezomib allowed

- More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
and recovered

- More than 4 weeks since prior immunotherapy or biologic therapy

- More than 2 weeks since prior steroid therapy (group II only)

- No prior anti-vascular endothelial growth factor therapy

- More than 4 weeks since prior full-field radiotherapy (2 weeks for limited-field
radiotherapy)

- No prior radiation to > 25% of bone marrow

- More than 4 weeks since major surgery (e.g., laparotomy) (2 weeks for minor surgery)

- Insertion of a vascular access device is not considered major or minor surgery

- No concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary other
therapy considered investigational

- No concurrent prophylactic colony-stimulating factors

- No concurrent therapeutic anticoagulation

- Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) of venous or
arterial access devices allowed provided requirements for PT, INR, or PTT are
met

- No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin,
carbamazepine, and phenobarbital), rifampin, or Hypericum perforatum (St. John's
Wort)

- No concurrent participation in any other study involving a pharmacologic agent (e.g.,
drugs, biologics, immunotherapy, or gene therapy), either for symptom control, or
therapeutic intent

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD as assessed by the number of patients with dose-limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)

Outcome Description:

DLTs include: Hematologic: Grade 4 ANC for ≥5 days, Grade 4 anemia of any duration, or PLT <25,000 of any duration; Renal: Serum creatinine ≥2 times baseline or > 2x upper limit of normal if baseline levels normal; All other non-hematologic toxicities ≥grade 3 as per CTCAE v3.0 except fatigue; Any toxicities that caused dose delay of > 2 weeks of the intended next dose. MTD is the dose level below the lowest dose that induces DLT in at least one-third of patients (2 of 6 patients).

Outcome Time Frame:

Observed for at least 3 weeks at a given dose level combination

Safety Issue:

Yes

Principal Investigator

Shaji Kumar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00124

NCT ID:

NCT00303797

Start Date:

December 2005

Completion Date:

Related Keywords:

  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Multiple Myeloma
  • Stage III Multiple Myeloma
  • Stage IV Chronic Lymphocytic Leukemia
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Mayo ClinicRochester, Minnesota  55905