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A Phase II Study of the c-Met Inhibitor ARQ 197 in Patients With Relapsed, or Relapsed and Refractory Multiple Myeloma


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

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Trial Information

A Phase II Study of the c-Met Inhibitor ARQ 197 in Patients With Relapsed, or Relapsed and Refractory Multiple Myeloma


PRIMARY OBJECTIVES:

I. To determine the overall response rate of patients with relapsed, or relapsed and
refractory multiple myeloma treated with the c-Met inhibitor ARQ 197 (tivantinib) as a
single agent.

II. To define the toxicities of single agent ARQ 197 in a population of patients with
relapsed, or relapsed and refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To obtain preliminary evidence of the durability of responses to single agent ARQ 197,
including the progression free survival (PFS), the duration of response (DOR), and the time
to next treatment (TTNT) II. To correlate the activation status of the HGF/c-Met pathway in
primary myeloma cells at baseline, as defined by gene expression profiling and reverse phase
protein array data, with the above measures of efficacy of ARQ 197.

III. To correlate serum and marrow HGF, HGF activator (HGFA), and soluble c-Met (sc-Met)
levels with the activation status of the HGF/c-Met pathway in primary myeloma cells at
baseline, and with the above measures of efficacy of ARQ 197.

EXPLORATORY OBJECTIVES I. To evaluate the symptom burden of relapsed, or relapsed and
refractory multiple myeloma patients undergoing therapy with single agent ARQ 197 using the
M. D. Anderson Symptom Inventory (MDASI) and its multiple myeloma module (MDASI-MM) II. To
evaluate the impact of therapy with single agent ARQ 197 for relapsed, or relapsed and
refractory multiple myeloma on patient reported outcomes using the European Organization for
Research on the Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30
(QLQ-C30), and the myeloma-specific module QLQ-MY20.

III. To evaluate the impact of therapy with single agent ARQ 197 for relapsed, or relapsed
and refractory multiple myeloma on the ability to collect stem cells in any patients who go
on to undergo subsequent stem cell mobilization.

OUTLINE:

Patients receive c-Met inhibitor ARQ 197 (tivantinib) orally (PO) twice daily (BID) on days
1-28. Courses continue every 28 days in the absence of disease progression or unacceptable
toxicity. Patients undergo blood, urine, and bone marrow collection for gene expression
profile, proteomic profiling, and other correlative studies. Patients may complete the M. D.
Anderson Symptom Inventory (MDASI) and its multiple myeloma module (MDASI-MM), the European
Organization for Research on the Treatment of Cancer (EORTC) Quality of Life Questionnaire
(QLQ) Core 30 (QLQ-C30), and the myeloma-specific module QLQMY20 questionnaires at baseline
and periodically during study.

After completion of study treatment, patients are followed up for 30 days.


Inclusion Criteria:



- Patients must have been previously diagnosed with histologically or cytologically
confirmed symptomatic multiple myeloma, which requires the presence of all three of
the following International Myeloma Working Group criteria, except as noted:

- Clonal bone marrow plasma cells ≥ 10%

- A monoclonal protein in either serum or urine

- Evidence of end-organ damage that can be attributed to the underlying plasma
cell proliferative disorder (to include one of the following):

- Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL)

- Renal insufficiency attributable to myeloma (serum creatinine > 1.9 mg/dL)

- Anemia; normochromic, normocytic with a hemoglobin value ≥ 2 g/dL below the
lower limit of normal, or a hemoglobin or < 10 g/dL

- Bone lytic lesions, severe osteopenia, or pathologic fractures

- Patients with a biopsy-proven plasmacytoma and either a serum or urine
monoclonal protein will also be considered to have met the diagnostic
criteria for multiple myeloma in the absence of clonal marrow plasmacytosis
of >= 10%, but must still meet the criteria for evidence of end-organ
damage

- Patients must have measurable disease, as defined by at least one of the following:

- Serum monoclonal protein level ≥ 0.5 g/dL for IgG, IgA, or IgM disease

- Monoclonal protein or total serum IgD ≥ 0.5 g/dL for IgD disease

- Urinary M-protein excretion of ≥ 200 mg over a 24-hour period

- Involved free light chain level ≥ 10 mg/dL, along with an abnormal free light
chain ratio

- Patients must have had at least one, but not more than four prior lines of therapy
for their disease, with lines of therapy being separated by the presence of
documented disease progression;

- Using this definition, treatment with induction therapy, followed by high-dose
chemotherapy and autologous stem cell transplantation, and finally by
maintenance therapy,would constitute one line, provided that multiple myeloma
did not meet criteria for progression at any time during this period

- Patients must have disease that has relapsed after their most recent therapy, with
progressive disease (PD) being defined as an increase of 25% from the lowest response
value in any one or more of the following:

- Serum M-component (the absolute increase must be ≥ 0.5 g/dL)

- Urine M-component (the absolute increase must be ≥ 200 mg/24 hours)

- Only in patients without a measurable serum and urine M protein level: the
difference between involved and uninvolved FLC levels (absolute increase) must
be > 10 mg/dL

- Definite development of new bone lesions or soft tissue plasmacytomas or
definite increase in the size of existing bone lesions or soft tissue
plasmacytomas

- Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be
attributed solely to the plasma cell proliferative disorder

- Patients with relapsed disease will be considered to be those who have had
progression, as defined above, off of any therapy, and who completed their
therapy more than 60 days prior to the finding of progression; patients with
relapsed and refractory disease will be considered to be those who have had
progression, as defined above, while still on their last line of therapy, or who
progressed within 60 days of finishing their most recent therapy

- Patients who have known central nervous system involvement with multiple myeloma will
be excluded from this clinical trial

- No patients with non-secretory multiple myeloma, active plasma cell leukemia (defined
as either having 20% of peripheral white blood cells comprised of CD138+ plasma
cells, or an absolute plasma cell count of 2 x 10^9/L), known amyloidosis, or known
POEMS syndrome(plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin changes)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
(Karnofsky≥ 60%)

- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3 without growth factors within 1
week of the initiation of treatment

- Total white blood cell count (WBC) ≥ 2,000 cells/mm^3 without growth factors within
1week of the initiation of treatment

- Hemoglobin ≥ 8 g/dL without red blood cell transfusions within 2 weeks of the
initiation of treatment

- Platelet counts of ≥ 100,000 cells/mm^3 for patients who have bone marrow
plasmacytosis of < 50%, or ≥ 50,000 cells/mm^3 for patients who have bone marrow
plasmacytosis of≥ 50%

- Total bilirubin ≤ 1.5 times the upper limit of the institutional normal (ULN) values

- Total AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN values

- Serum creatinine within the institutional normal limits OR creatinine clearance
(CrCl) ≥ 30 mL/min

- Patients must have evidence of adequate cardiac function, as defined by the
following:

- Absence of New York Heart Association (NYHA) class II, III, or IV congestive
heart failure

- Absence of uncontrolled angina or hypertension

- Absence of myocardial infarction in the previous 6 months

- Absence of clinically significant bradycardia or other uncontrolled cardiac
arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0

- HIV-seropositive patients with acceptable organ function who meet the patient
selection criteria, and who are not on combination antiretroviral therapy, and whose
absolute CD4+ coun tis ≥ 400 cells per cubic millimeter of blood, will be eligible

- Male patients must agree to use an adequate method of contraception for the duration
of the study

- Female patients must be either post menopausal, free from menses for ≥ 2 years,
surgically sterilized, or willing to use two adequate barrier methods of
contraception to prevent pregnancy, or must agree to abstain from heterosexual
activity throughout the study

- Negative serum pregnancy test

- Pregnant or lactating women are excluded from this study

- No patients with a known history of allergic reactions attributed to compounds of
similar chemical or biologic composition to ARQ 197

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements, in the opinion of the Principal Investigator

- No patients with known active hepatitis A, B, and/or C infection

- No patients with a "currently active" second malignancy, other than non-melanoma
skincancer and carcinoma in situ of the cervix, should not be enrolled

- Patients are not considered to have a "currently active" malignancy if they have
completed therapy for a prior malignancy,are disease free from prior
malignancies for > 5 years, and are considered by their physician to be at less
than 30% risk of relapse

- Patients with basal cell carcinoma of the skin,superficial carcinoma of the
bladder, carcinoma of the prostate with a current PSA value of < 0.5ng/mL, or
cervical intraepithelial neoplasia will be eligible

- Patients who are on hormonaltherapy for a history of either prostate cancer or
breast cancer may enroll, provided that there has been no evidence of disease
progression during the previous three years

- No other concurrent anticancer therapies including, but not limited to, chemotherapy,
radiotherapy, hormonal therapy (except megestrol acetate as supportive care),
immunotherapy, or locoregional therapy

- Patients must have completed their most recent drug therapy directed at multiple
myelomain the following time frames:

- Chemotherapy, biological therapy, immunotherapy, or an investigational therapy
at least3 weeks prior to starting c-Met inhibitor ARQ197 (ARQ 197)

- Corticosteroids at least 3 weeks prior to starting ARQ 197, except for a dose
equivalent to dexamethasone of ≤ 4 mg/day

- Nitrosoureas, nitrogen mustards, mitomycin C, or monoclonal antibodies at least
6weeks prior to starting ARQ 197

- Autologous stem cell transplantation at least 12 weeks prior to starting ARQ 197

- Allogeneic stem cell transplantation at least 24 weeks prior to starting ARQ
197, and these patients must also not have moderate to severe active acute or
chronic graft-versus-host disease

- Patients who have received radiation therapy must have completed this at least 4
weeks prior to starting therapy with ARQ 197, with the following exceptions:

- Local radiation therapy to enhance bone healing of a pathologic fracture may
have been performed, as long as it was completed at least 2 weeks prior to
starting ARQ 197

- Local radiation therapy to treat post-fracture pain that is refractory to
analgesics may have been performed, as long as it was completed at least 2 weeks
prior to starting ARQ197

- Patients who have undergone any recent major surgery must have done so at least
4weeks prior to starting therapy with ARQ 197, with the following exceptions:

- Vertebroplasty and/or kyphoplasty, which must have been performed at least 1
week prior to starting ARQ 197

- Planned elective surgery unrelated to the patient's diagnosis of multiple
myeloma, such as hernia repair, may be allowed, at the discretion of the
Principal Investigator, as long as it was performed at least 2 weeks prior to
starting ARQ 197, and patients have recovered fully from this procedure

- HIV-positive patients on combination antiretroviral therapy will be ineligible

- No patients who are receiving any concurrent investigational agent with known or
suspected activity against multiple myeloma, or those whose adverse events due to
agents administered more than 4 weeks earlier have not recovered to a severity of
grade 0 or grade 1

- No patients who have previously been treated with another agent targeting the
HGF/c-Metaxis, including either monoclonal antibodies to HGF or c-Met, or small
molecule inhibitors of c-Met

- No patients who have required plasmapheresis and exchange less than 2 weeks prior to
initiation of therapy with ARQ 197

- No concurrent immunosuppressive therapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Overall response rate (ORR)

Outcome Description:

Will be estimated with a 95% credible interval. Summary statistics will be provided for continuous variables. The Wilcoxon rank sum test, or Fisher's exact test will be used to test the association between the response and the prognostic factors. Univariate and multivariate logistic regression models will be fit to identify clinical factors associated with overall response.

Outcome Time Frame:

Up to 30 days

Safety Issue:

No

Principal Investigator

Robert Orlowski

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-03470

NCT ID:

NCT01447914

Start Date:

November 2011

Completion Date:

Related Keywords:

  • Refractory Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030