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A Phase 1 Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Advanced Solid Tumors

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Trial Information

A Phase 1 Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors


The study is only enrolling patients in the expanded cohorts with hepatocellular carcinoma,
renal cell carcinoma, melanoma, non-small cell lung cancer, and breast cancer.

Enrollment of an initial patient cohort of 3 or 6 patients will follow the traditional "3 +
3" dose escalation scheme. These patients will be treated with ARQ 197 and sorafenib at
Dose Level 1 (ARQ 197 360 mg BID and sorafenib 200 mg BID). Enrollment of subsequent
patient cohort(s) will depend on the safety and tolerability of the combination treatment in
the initial cohort. If <33% patients treated at Dose Level 1 experience dose-limiting
toxicity(ies) (DLT) by the end of first treatment cycle (4 weeks), then next cohort of 6
patients will be enrolled and treated at Dose Level 2 (ARQ 197 360 mg BID and sorafenib 400
mg BID). If ≥ 33% patients treated at Dose Level 1 experience DLT(s) by the end of first
treatment cycle, the next cohort of 6 patients will be enrolled and treated at Dose Level 0
(ARQ 197 240 mg BID and sorafenib 200 mg BID).

Additional treatment cohorts may be enrolled to explore intermediate, higher or lower doses
of ARQ 197, as indicated by the tolerability, safety profile, and pharmacokinetic (PK)
profile.

Intra-patient dose-escalation from Dose Level 1 to Dose Level 2 may occur in patients
enrolled in Dose Level 1 after they complete at least 1 cycle of treatment without DLT and
other drug-related adverse event that, in the opinions of Investigator and Medical Monitor,
is serious and medically significant.

Once a safe and recommended dose level is determined, an expanded cohort (Expansion Cohort
1) of up to 40 patients with either unresectable HCC or advanced renal cell carcinoma (RCC),
for whom sorafenib is indicated, will be enrolled and treated at this dose level (expansion
portion). Up to 20 patients with unresectable HCC and up to 20 patients with advanced RCC
may be enrolled in this protocol (including patients in dose-escalation cohorts and
expansion cohort).

An additional expansion cohort (Expansion Cohort 2) of up to 40 patients with breast cancer,
non-small cell lung cancer or melanoma will be enrolled and treated at MTD/RP2D. Up to 10
patients may be enrolled for breast and non-small cell lung cancer and up to 20 patients
with melanoma (at least 10 of whom must have NRAS mutation).

Under Amendment #3, newly enrolled subjects with HCC will be given ARQ 197 at 240 mg BID as
starting dose. If a patient with HCC tolerates this starting dose for at least one cycle,
the investigator may increase his/her dose to 360 mg BID.


Inclusion Criteria:



- Written informed consent granted prior to initiation of any study-specific screening
procedures

- 18 year of age or older

- Histologically or cytologically confirmed locally advanced, inoperable or metastatic
solid tumors. In the two expansion cohorts, only patients with histologically or
cytologically confirmed HCC, RCC, breast cancer, NSCLC and melanoma are eligible. An
exception for this criterion is that patients with HCC may be enrolled without
histological confirmation of disease so long as they meet the following criteria for
diagnosis of HCC (and all other protocol eligibility criteria):

1. Lesion > 2cm in diameter

2. α-fetoprotein (AFP) > 200 ng/mL

3. Radiological appearance of mass is suggestive of HCC

- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1

- Adequate bone marrow, liver, and renal functions, defined as:

- Platelet count ≥ 100 × 10^9/L (≥ 60 × 10^9/L for HCC patients enrolled in the
expanded cohort)

- Hemoglobin ≥ 10 g/dL

- Absolute neutrophil count (ANC) ≥1.5 × 10^9/L

- Total bilirubin ≤ 1.5 mg/dL or ≤ 3 mg/dL with HCC or metastatic liver disease

- Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of
normal (ULN) or ≤ 5 × ULN with HCC or metastatic liver disease

- Serum creatinine ≤1.5 × ULN

- International normalized ratio (INR) 0.8 to 1.2 or 2 to 3 for patients receiving
anticoagulant such as coumadin or heparin. Patients who are therapeutically
anticoagulated are allowed to participate provided that no prior evidence of
underlying abnormality exists in these parameters

- Women of childbearing potential must have a negative pregnancy test performed within
seven days prior to the start of study drug

- Male and female subjects of child-bearing potential must agree to use double-barrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after last investigational drug dose received

Exclusion Criteria:

- Previous anti-cancer chemotherapy, radiotherapy, immunotherapy or investigational
agents within 4 weeks prior to the first day of study defined treatment with the
following exceptions: 1) a prostate cancer patient on androgen deprivation with
gonadotropin-releasing hormone (GnRH) agonists can be enrolled while he remains on
the immunotherapy; 2) a patient received palliative radiotherapy previous can be
enrolled if the therapy was completed 1 week (7 days) prior to the first day of study
defined treatment and the patient has recovered from any radiotherapy-related adverse
event(s); and 3) patients are currently on sorafenib can be enrolled

- History of cardiac disease: congestive heart failure defined as Class II to IV per
New York Heart Association (NYHA) classification; active coronary artery disease
(CAD); previously diagnosed clinically significant bradycardia, other uncontrolled
cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute
(NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0), or
uncontrolled hypertension; myocardial infarction occurred within 6 months prior to
study entry (myocardial infarction occurred > 6 months prior to study entry is
permitted)

- Active clinically serious infections defined as ≥ Grade 2 according to NCI CTCAE,
version 3.0

- Substance abuse, medical, psychological or social conditions that may, in the opinion
of the Investigator, interfere with the patient's participation in the study or
evaluation of the study results

- Any condition that is unstable or which could jeopardize the safety of the patient
and his/her protocol compliance

- Known human immunodeficiency virus (HIV) infection

- Pregnancy or breast-feeding

- Inability to swallow oral medications

- Significant gastrointestinal disorder, in the opinion of the Investigator, could
interfere with the absorption of ARQ 197 and/or sorafenib (e.g. significant,
uncontrolled inflammatory bowel disease or extensive small bowel resection).

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To identify maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ARQ 197 when administered in combination with sorafenib.

Outcome Time Frame:

6 to 9 months. Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

ARQ 197-116

NCT ID:

NCT00827177

Start Date:

September 2009

Completion Date:

June 2013

Related Keywords:

  • Advanced Solid Tumors
  • dose escalation
  • safety
  • tolerability
  • tumor
  • PK
  • hepatocellular carcinoma
  • renal cell carcinoma
  • melanoma
  • non-small cell lung cancer
  • breast cancer
  • Neoplasms

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Nashville, Tennessee  37203-1632
Boston, Massachusetts