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A Phase 1 Study of ARQ 197 in Combination With Temsirolimus in Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1 Study of ARQ 197 in Combination With Temsirolimus in Advanced Solid Tumors


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
ARQ197 in combination with temsirolimus in adult subjects with advanced solid tumors who are
extensive cytochrome P450 2C19 (CYP2C19) metabolizers.

SECONDARY OBJECTIVES:

I. To characterize the tolerability and/or MTD of ARQ 197 and in combination with
temsirolimus in adult subjects who are poor CYP2C19 metabolizers (CYP2C19*2/*2, *2/*3 or
*3/*3 polymorphisms).

II. To identify the pharmacokinetic parameters of ARQ 197 after a single dose and at steady
state in extensive and poor CYP2C19 metabolizers.

III. To assess the steady state pharmacokinetics of ARQ 197 alone and in combination with
temsirolimus.

IV. To determine impact of CYP3A4/5 polymorphisms on ARQ 197 pharmacokinetic parameters.

V. To determine the pharmacokinetics of temsirolimus and its active metabolite sirolimus in
combination with ARQ 197 and compare to historical pharmacokinetic data.

VI. To determine impact of CYP3A4/5 polymorphisms on temsirolimus pharmacokinetic
parameters.

VII. To describe the dose-limiting toxicities and determine the safety profile of the
combination of ARQ 197 and temsirolimus.

VIII. To evaluate the preliminary anti-tumor activity of ARQ197 and temsirolimus in patients
with advanced solid tumors.

IX. To assess for pharmacodynamic evidence of c-Met and mammalian target of rapamycin (mTOR)
inhibition in peripheral blood mononuclear cells (PBMCs) over the course of therapy.

X. To correlate archived tumor tissue expression of c-Met with objective response to ARQ 197
and temsirolimus therapy.

OUTLINE: This is a dose-escalation study of tivantinib.

Patients receive tivantinib orally (PO) twice daily (BID) and temsirolimus intravenously
(IV) over 30 minutes on days 1, 8, 15, and 22 (days 8, 15, 22, and 29 of course 1). Courses
repeat every 28 days (35 days in course 1) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 4 weeks.


Inclusion Criteria:



- Patients must have histologically confirmed solid malignancy (excluding lymphoma)
that is metastatic or unresectable and for which standard curative or palliative
systemic therapies (such as chemotherapy, targeted therapies or immunotherapy) do not
exist or are no longer effective

- Patients must have measurable or evaluable disease, as defined by Response Evaluation
Criteria In Solid Tumors (RECIST) 1.1

- No prior treatment with temsirolimus or an agent specifically targeting c-Met

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Hemoglobin >= 9.0 g/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Serum creatinine =< institutional upper limit of normal or creatinine clearance
(either estimated or calculated) >= 60 mL/min/1.73 m for patients with creatinine
levels above institutional normal

- Fasting glucose =< 150 mg/dL

- Fasting cholesterol level < 350 mg/dl

- Fasting triglycerides =< 300 mg/dl

- Phosphorus >= institutional lower limit of normal (repletion allowed)

- Patients with treated, stable brain metastases are allowed to enroll; patients must
be at least 4 weeks from radiation and off any medications used to treat brain
metastases including steroids; patients are allowed to be on antiepileptic
medications that are not metabolized by cytochrome P450 3A4 or 2C19; patients with
brain metastases must have stable brain imaging within 4 weeks prior to starting
study

- The effects of ARQ 197 and temsirolimus on the developing human fetus are unknown;
for this reason and because tyrosine kinase inhibitors as well as other therapeutic
agents used in this trial are known to be potentially teratogenic, women of
child-bearing potential must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, for the duration of study
participation and up to 3 months after discontinuation of study drugs; men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 4 months after completion of ARQ
197 administration; should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Any of the following:

- Chemotherapy =< 3 weeks prior to entering the study (6 weeks for nitrosoureas or
mitomycin C)

- Radiotherapy, endocrine therapy or targeted therapy for malignancy =< 2 weeks
prior to registration

- Patients who have not recovered (=< grade 1) from adverse events due to agents
administered more than 4 weeks earlier (tolerable grade 2 adverse events may be
allowed at the discretion of the investigator)

- Prior anticancer therapy with an mTOR inhibitor (everolimus, temsirolimus,
desferolimus) or agent specifically targeting c-Met

- Patients who are receiving any other investigational agents

- Patients may not have clinically symptomatic hypothyroidism; testing is not required
for eligibility

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ARQ 197 or temsirolimus

- ARQ 197 is a sensitive substrate for 2C19 and 3A4, a strong inhibitor for 2C19 and
moderate inhibitor by in vitro data only for 3A4; temsirolimus is a sensitive
substrate for CYP 3A4 and a weak inhibitor of CYP2D6 and CYP3A4/5; per the UWinRx
Drug Interaction Policy, the following medications are contraindicated or must be
used with caution

- Contraindicated:

- CYP2C19 sensitive substrates (unless close monitoring with labs or drug levels
with dose adjustments is feasible), inducers, and moderate/strong inhibitors of
CYP2C19; patients taking these concurrent medications are ineligible unless they
can be switched to alternative medications prior to initiation of the study

- CYP3A4/5 inducers and moderate/strong inhibitors of CYP3A4/5; patients taking
these concurrent medications are ineligible unless they can be switched to
alternative medications prior to initiation of the study

- Use with Caution:

- CYP2C19 non-sensitive substrates with a narrow therapeutic window and weak
inhibitors are permitted if no acceptable alternatives are available as
determined by the treating physician; however, caution should be used; consider
monitoring with labs or drug levels and dose adjustments of the medication if
feasible; other non-sensitive substrates are allowed on study

- CYP3A4/5 sensitive substrates and any non-sensitive substrates with a narrow
therapeutic window and weak inhibitors are permitted if no acceptable
alternatives are available as determined by the treating physician; however,
caution should be used; consider monitoring with labs or drug levels and dose
adjustments of the medication if feasible; other non-sensitive substrates are
allowed on study

- CYP2D6 inducers, moderate/strong inhibitors or sensitive substrates are
permitted if no acceptable alternatives are available; however, caution should
be used; other non-sensitive substrates or weak inhibitors of CYP2D6 are allowed
on study

- History of congestive heart failure defined as Class II to IV per New York Heart
Association (NYHA) classification; active coronary artery disease (CAD); clinically
significant bradycardia (< 50 beats per minute [bpm]) or other uncontrolled, cardiac
arrhythmia defined as ≥ grade 3 according to National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled
hypertension (as determined by the investigator); myocardial infarction occurring
within 6 months prior to study entry (myocardial infarction occurring >6 months prior
to study entry is permitted)

- Patients with uncontrolled diabetes (as determined by the investigator);
well-controlled diabetic patients with fasting glucose < 150 are eligible if they
have been on stable doses of medications for diabetes for at least 4 weeks prior to
study entry

- 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

- Pregnant women are excluded from this study because ARQ 197 is a tyrosine kinase
inhibitor with the potential for teratogenic or abortifacient effects; the safety of
temsirolimus in pregnancy has also not been established; because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with ARQ 197 and/or temsirolimus, breastfeeding should be discontinued if
the mother is treated on this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
ARQ 197 and temsirolimus; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption of pills; patients must be able to swallow pills

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD and RP2D of tivantinib in combination with temsirolimus defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) and two or more patients have experienced a DLT at the next higher dose level

Outcome Description:

Categorized according to NCI Common Toxicity Criteria version 4.0.

Outcome Time Frame:

First 35 days

Safety Issue:

No

Principal Investigator

Kari Wisinski

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00949

NCT ID:

NCT01625156

Start Date:

May 2012

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Wisconsin Clinical Cancer CenterMilwaukee, Wisconsin  53226