Advanced Solid TumorsPhase 1NCT00827177
Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors
A Phase 1 study testing Treatment with ARQ 197 in combination with sorafenib in people with Advanced Solid Tumors, run by ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) at 4 sites in 2 countries.
Trial summary
This is an open-label, dose-escalation study of ARQ 197 administered orally in combination with sorafenib. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumors
- What is being tested?
- Treatment with ARQ 197 in combination with sorafenib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 87 participants
- Where
- 4 sitesin 2 countries
- Study dates
- Sep 2009to May 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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):
- Lesion > 2cm in diameter
- α-fetoprotein (AFP) > 200 ng/mL
- Radiological appearance of mass is suggestive of HCC
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- 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
Who cannot join
- 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
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- 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).
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States3 sites
Study site
Boston, Massachusetts, 02111
Roswell Park Cancer Institute
Buffalo, New York, 14263
Study site
Nashville, Tennessee, 37232
About this study
Official title: A Phase 1 Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors
This is an open-label, dose-escalation study of ARQ 197 administered orally in combination with sorafenib.
Read the detailed description
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.
- Conditions
- Advanced Solid Tumors
- Being tested
- Treatment with ARQ 197 in combination with sorafenib
- Keywords
- dose escalation, safety, tolerability, tumor, PK, hepatocellular carcinoma, renal cell carcinoma, melanoma, non-small cell lung cancer, breast cancer
- Medical subject headings
- Neoplasms, Carcinoma, Hepatocellular, Carcinoma, Renal Cell, Melanoma, Carcinoma, Non-Small-Cell Lung, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Treatment with ARQ 197 in combination with sorafenibDrug
Patients will be treated with ARQ 197 and sorafenib at Dose Level 1 (ARQ 197 360 mg twice daily (bid) and sorafenib 200 mg bid). Patients with HCC will start treatment with ARQ 197 at 240 mg bid and sorafenib 200 mg bid. Enrollment of subsequent patient cohort 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).
| Study group | Role | What they receive |
|---|---|---|
| ARQ 197 in combination with sorafenib | Experimental | Not described Receives: Drug: Treatment with ARQ 197 in combination with sorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
To identify maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ARQ 197 when administered in combination with sorafenib.
Measured: 6 to 9 months. Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
Secondary outcomes (3)
To determine the pharmacokinetic profiles of ARQ 197 and sorafenib.
Measured: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
To assess the preliminary anti-tumor activity of ARQ 197 when administered in combination with sorafenib.
Measured: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
To evaluate dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood that are associated with treatment of ARQ 197 plus sorafenib.
Measured: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2009 (estimated)
- Study startSep 2009
- Primary completionSep 2012
- Study completionMay 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Solid TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 87 participants (actual)
Sponsor and investigators
- Lead sponsor
- ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00827177
- Sponsor's protocol ID
- ARQ 197-116
- Status last verified
- Jan 2014
- First submitted
- 21 Jan 2009
- Last updated
- 24 Jan 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Jan 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT00827177
- Acronym / sponsor ID
- ARQ 197-116
- Conditions
- Advanced Solid Tumors
- Keywords
- dose escalation, safety, tolerability, tumor, PK, hepatocellular carcinoma, renal cell carcinoma, melanoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 87 participants (actual)
- Lead sponsor
- ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)Industry (pharma, biotech, devices)
- Study start
- Sep 2009
- Primary completion
- Sep 2012 (actual)
- Study completion
- May 2013 (actual)
- First posted
- 22 Jan 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open-label, dose-escalation study of ARQ 197 administered orally in combination with sorafenib.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ARQ 197 in combination with sorafenib | Experimental | Drug: Treatment with ARQ 197 in combination with sorafenib |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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):
- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Treatment with ARQ 197 in combination with sorafenibPatients will be treated with ARQ 197 and sorafenib at Dose Level 1 (ARQ 197 360 mg twice daily (bid) and sorafenib 200 mg bid). Patients with HCC will start treatment with ARQ 197 at 240 mg bid and sorafenib 200 mg bid. Enrollment of subsequent patient cohort 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). | Drug | ARQ 197 in combination with sorafenib |
Primary outcome
To identify maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ARQ 197 when administered in combination with sorafenib.
Time frame: 6 to 9 months. Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
3 secondary outcomes
To determine the pharmacokinetic profiles of ARQ 197 and sorafenib.
Time frame: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
To assess the preliminary anti-tumor activity of ARQ 197 when administered in combination with sorafenib.
Time frame: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
To evaluate dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood that are associated with treatment of ARQ 197 plus sorafenib.
Time frame: Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jan 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Treatment with ARQ 197 in combination with sorafenib in people with Advanced Solid Tumors, run by ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jan 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To identify maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ARQ 197 when administered in combination with sorafenib. (time frame: 6 to 9 months. Patients will remain on study until progression of disease, unacceptable toxicity, or other discontinuation criterion is met.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jan 2014.