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

Phase 1
18 Years
Not Enrolling
Advanced Solid Tumors

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Trial Information

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

Enrollment of an initial cohort of 3 or 6 patients will follow the traditional "3 + 3" dose
escalation scheme. These patients will be treated with ARQ 197 and gemcitabine. ARQ 197 will
be administered by mouth BID continuously. Gemcitabine will be administered by intravenous
infusion over 30 minutes once weekly for 3 consecutive weeks followed by a week of rest. The
dosing schedules of ARQ 197 and gemcitabine will be as described below.

ARQ 197 will be administered per the following cohorts, starting from week 1 of treatment.

Cohort------ARQ 197 (mg BID)

0-----------120, continuously

1-----------240, continuously

A-----------120 (repeated treatments of 2 weeks followed by a 1 week pause)

B-----------240 (repeated treatments of 2 weeks followed by a 1 week pause)

C-----------360 (repeated treatments of 2 weeks followed by a 1 week pause)

D-----------360 (repeated treatments of 3 weeks followed by a 1 week pause)

E-----------360, continuously

In case of DLT, intermediate dosing cohorts will be explored, administering ARQ 197 for 5
days instead of 7 during the weeks of ARQ 197 administration.

For cohorts 0 and 1, gemcitabine is administered at the dose of 1000mg/sqm from week 1 of
treatment, 4 weeks in a row for the first month, then for 3 consecutive weeks followed by a
week of pause. For all other cohorts, gemcitabine will be administered starting from week 2
of treatment at the dose of 1000mg/sqm, for 3 consecutive weeks followed by a week of pause.

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)

Once a safe and recommended dose level is determined, an Expanded Cohort of up to 60
patients with non-resectable cholangiocarcinoma (10 patients), breast carcinoma (10
patients), ovarian carcinoma (10 patients), endometrial carcinoma and carcinoma of the
cervix (10 patients in total, at least five with endometrial carcinoma). Each group of 10
patients may enroll up to three patients who received at least 5-week gemcitabine treatment.
The cohort will also include up to 20 patients with pancreatic carcinoma (up to five out of
20 patients may have received at least 5-week gemcitabine treatment).

Inclusion Criteria:

- Written informed consent granted prior to initiation of any study-specific screening
procedures, given with the understanding that the patient has the right to withdraw
from the study at any time, without prejudice

- 18 year of age or older

- Histologically or cytologically confirmed locally advanced, inoperable or metastatic
primary solid tumors

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

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

- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of
normal (ULN) or ≤ 5 x ULN with metastatic liver disease

- Hemoglobin ≥ 10 g/dl (or ≥ 9 g/dl for expanded cohort)

- Total bilirubin ≤ 1.5 x ULN

- Serum creatinine ≤ 1.5 x ULN

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

- Platelets ≥ 100 x 10^9/L

- 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:

- Other cancer within the last three years, with the exception of adequately treated
cone-biopsied in situ carcinoma of the cervix uteri or basal or squamous cell
carcinoma of the skin

- Previous anti-cancer chemotherapy, radiotherapy, major surgery, immunotherapy or
investigational agents within 4 weeks prior to the first day of study defined

- 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 bradycardia or other 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 gemcitabine (e.g. significant,
uncontrolled inflammatory bowel disease or extensive small bowel resection)

- Central nervous system metastases

Type of Study:


Study Design:

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

Outcome Measure:

To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of ARQ 197 when administered in combination with gemcitabine.

Outcome Time Frame:

Patients will remain on study until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.

Safety Issue:



United States: Food and Drug Administration

Study ID:

ARQ 197-117



Start Date:

March 2009

Completion Date:

April 2011

Related Keywords:

  • Advanced Solid Tumors
  • dose escalation
  • safety
  • tolerability
  • tumor
  • PK
  • Neoplasms



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