Advanced Solid TumorsPhase 1NCT01999972
A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors
A Phase 1 study testing axitinib and crizotinib in people with Advanced Solid Tumors, run by Pfizer at 17 sites in 2 countries.
Trial summary
Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment, while the majority of patients will eventually develop evasive resistance. 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?
- axitinib and crizotinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 17 sitesin 2 countries
- Study dates
- 26 Feb 2014to 5 Sep 2019
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Diagnosis - Dose Escalation Phase: Histologically or cytologically confirmed diagnosis of advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available.
- Diagnosis - Dose Expansion Phase: Histologically or cytologically confirmed advanced RCC with a component of clear cell subtype
- Dose Expansion Phase: at least one measureable lesion as defined by RECIST [Response Evaluation Criterion in Solid Tumors] version 1.1.
- ECOG [Eastern Cooperative Oncology Group] Performance Status 0 or 1.
Who cannot join
- Major surgery <4 weeks or radiation therapy <2 weeks of patient registration.
- History of or known active seizure disorder, brain metastases, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
- Dose Expansion Phase only: diagnosis of any other malignancy within 2 years prior to registration.
Trial locations and contacts
17 sites in 2 countries.
17 sites in 2 countries
United States15 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
University of Chicago Medical Center
Chicago, Illinois, 60637
Cleveland Clinic Taussig Cancer Center Investigational Pharmacy
Cleveland, Ohio, 44106
Wayne State University, Dept. of Oncology
Detroit, Michigan, 48201
Investigational Drug Services IUHSCC
Indianapolis, Indiana, 46202
IU Health University Hospital
Indianapolis, Indiana, 46202
University Station Ophthalmology Clinic
Madison, Wisconsin, 53705
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
University of Minnesota Health Clinics and Surgery Center
Minneapolis, Minnesota, 55455
University of Minnesota Medical Center, Fairview IDS Pharmacy
Minneapolis, Minnesota, 55455
University of Minnesota Medical Center, Fairview
Minneapolis, Minnesota, 55455
University of Minnesota Physicians Masonic Cancer Center
Minneapolis, Minnesota, 55455
Huntsman Cancer Hospital
Salt Lake City, Utah, 84112
Huntsman Cancer Institute
Salt Lake City, Utah, 84112
John A Moran Eye Center
Salt Lake City, Utah, 84132
United Kingdom2 sites
St Bartholomew's Hospital - Barts Health NHS Trust
London, EC1A 7BE
The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital
London, SW3 6JJ
About this study
Official title: A PHASE 1B, OPEN LABEL, DOSE ESCALATION STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH CRIZOTINIB (PF-02341066) IN PATIENTS WITH ADVANCED SOLID TUMORS
Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment, while the majority of patients will eventually develop evasive resistance. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute to VEGF inhibitor resistance, such that combining a c-MET inhibitor with a VEGF inhibitor will provide additional clinical activity compared to VEGF inhibitor alone. This hypothesis will be tested using the cMET/ALK inhibitor, crizotinib, in combination with the VEGF inhibitor, axitinib.Since this will be the first study of axitinib given in combination with crizotinib, the study will primarily assess the safety and tolerability of the combination regimen.
- Conditions
- Advanced Solid Tumors
- Being tested
- axitinib, crizotinib
- Keywords
- Carcinoma, Renal Cell
- Medical subject headings
- Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
axitinibDrug
Axitinib: tablets, dosage range 2 - 5 mg, given orally twice daily on a continuous dosing schedule in 28 days cycles.
crizotinibDrug
Crizotinib: capsules, dosage range 200-250 mg, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.
axitinibDrug
Axitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles.
crizotinibDrug
Crizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.
axitinibDrug
Axitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles.
crizotinibDrug
Crizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.
| Study group | Role | What they receive |
|---|---|---|
| Axitinib in combination with crizotinib, escalation phase | Experimental | Dose Escalation Advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available Receives: Drug: axitinib; Drug: crizotinib |
| Expansion Phase Cohort 1 | Experimental | Dose Expansion, Cohort 1: axitinib in combination with crizotinib Advanced renal cell cancer [RCC] with no prior systemic therapy Receives: Drug: axitinib; Drug: crizotinib |
| Expansion Phase Cohort 2 | Experimental | Dose Expansion, Cohort 2: axitinib in combination with crizotinib Advanced renal cell cancer with at least one but no more than two prior systemic treatment regimens directed at advanced RCC Receives: Drug: axitinib; Drug: crizotinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
Toxicity as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. DLT defined as any following events attributable to any (axitinib or crizotinib) or both agents in combination: hematologic (Grade 4 neutropenia, absolute neutrophil count<1000/mm^3 with single temperature of >38.3 degrees celsius or sustained temperature of 38 degrees celsius for >1 hour; >=Grade 3 neutropenic infection; >=Grade 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia), non-hematologic (>=Grade 3 toxicities [except asymptomatic hypophosphatemia, hyperuricemia without signs, symptoms of gout, and tumor lysis syndrome], nausea, vomiting or diarrhea persisted at Grade 3 or 4 despite maximal medical therapy; Grade 3 hypertension if persistent despite anti-hypertensives); In asymptomatic participant, Grade 3 QTc prolongation (QTc>=501 msec) if persisted after correcting reversible causes, and failure to deliver >=75 percent (%) of dose of each study drug.
Measured: Cycle 1 (28 days)
Secondary outcomes (23)
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drugs (crizotinib and axitinib) without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
Measured: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Treatment-related AE was any untoward medical occurrence attributed to study drugs (crizotinib and axitinib) in a participant who received study drugs. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
Measured: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Grade 3 or Higher Adverse Events (AEs) as Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
An AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 = death. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
Measured: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematological Test Abnormalities
Laboratory parameters included hematological and biochemistry parameters. Hematological parameters included haemoglobin (anemia, haemoglobin increased), lymphocytes (lymphopenia, lymphocyte count increased), neutrophils, platelets and white blood cells. Number of participants with hematological abnormalities by grades (as per NCI CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
Measured: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Biochemistry Test Abnormalities
Laboratory parameters included hematological and biochemistry parameters. Biochemistry parameters/abnormalities included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia and gamma glutamyl transferase Number of participants with biochemistry test abnormalities by grades (NCI CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.
Measured: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment Visit
Measured: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Pulse Rate at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment
Measured: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Body Weight at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment
Measured: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) to Worst Value
ECOG-PS: used to assess how disease affected the daily living abilities of participant. It ranges on the scale from: 0-5 (0=fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity but ambulatory/able to carry out light/sedentary work;2=ambulatory [for more than (>)50%of waking hours], capable of all self-care but unable to carry out any work activities;3=capable of limited self-care, confined to bed or chair [for >50% of waking hours];4=completely disabled, not capable of any self-care, totally confined to bed or chair;5= dead, higher score=more functional impairment) and changes to worst status scores were presented. Baseline value=value collected prior to first dose of study drug on Cycle 1 Day 1. Worst post-baseline value=worst value between first dose of any study drug and end of treatment (EOT) visit. Shift to low refers to lower than Baseline value; shift to high refers to higher than baseline value for ECOG-PS.
Measured: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
Number of Participants With Maximum Increase From Baseline in QTc Interval
Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Number of participants with maximum increase from baseline of less than (<) 30 milliseconds (msec), 30 to <60 msec and greater than or equal to (>=) 60 msec were reported.
Measured: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
Maximum Observed Plasma Concentration (Cmax) of Axitinib and Crizotinib
Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.
Measured: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Crizotinib
Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.
Measured: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Axitinib and Crizotinib
Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours. Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.
Measured: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Apparent Oral Clearance (CL/F) of Axitinib and Crizotinib
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent oral clearance was obtained by dividing study drug dose with AUCtau, where AUCtau was area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval. Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.
Measured: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Apparent Volume of Distribution (Vz/F) of Axitinib and Crizotinib
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Measured: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Percentage of Participants With Objective Response
Percentage of participants with objective response based on assessment of confirmed complete response [CR] or confirmed partial response [PR] according to Response Evaluation Criteria In Solid Tumors [RECIST] version1.1 were reported. Confirmed responses were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent.
Measured: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Dose Expansion Part: Duration of Response
Duration of response (as per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was defined as the time (in months) from first documentation of objective tumor response (complete response [CR] or partial response [PR]) until the first date that recurrent, progressive disease, or death (whichever occurred first). CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent. Progression was defined as >= 20 percent increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions.
Measured: From first objective response until first recurrent, disease progression, or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
Dose Expansion Part: Progression-Free Survival (PFS)
PFS (as per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was defined as the time (in months) from start of study treatment to first documentation of objective tumor progression or death due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date minus date of first dose of study medication plus 1) divided by 30.44. Progression was defined as >= 20 percent increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions. PFS was not estimated in Dose Expansion Cohort 2 due to small sample size.
Measured: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Levels of Serum Soluble Protein Biomarkers
Serum soluble protein biomarkers included angiopoietin-2, Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor Receptor 3 (VEGFR 3). Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.
Measured: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Change From Baseline in Serum Concentration of Circulating microRNAs (miRNA) at End of Treatment
Measured: Baseline, end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Percentage of c-MET Positive Tumor Cell at Baseline in Relation to Objective Response Rate (ORR)
Percentage of c-MET positive tumor cell for objective response (complete response [CR] + partial response [PR]) is reported. Objective response was defined as CR and PR. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.
Measured: Baseline
Dose Expansion Part Cohort 1: Level of Plasma Soluble Protein Biomarker (c-MET)
Plasma soluble protein biomarker included c-MET. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.
Measured: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 5; end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Ratio of Serum Soluble Protein Biomarkers Level to Baseline Biomarkers Level by Each Timepoint
Serum soluble protein biomarkers included angiopoietin-2, Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor Receptor 3 (VEGFR3). Ratio=value of serum soluble protein biomarkers at each time point to the value at baseline. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.
Measured: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2013 (estimated)
- Study start26 Feb 2014
- Primary completion22 Feb 2017
- Study completion5 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Advanced Solid TumorsStudies of the same condition, open and under way.
- More trials run by PfizerThe sponsor's other registered studies.
- 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
- Non-randomised
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pfizer
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Pfizer CT.gov Call Center, Study director, Pfizer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01999972
- Sponsor's protocol ID
- A4061068
- Other IDs
- 2015-001724-31, 2015
- Status last verified
- Sep 2020
- First submitted
- 26 Nov 2013
- Last updated
- 24 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.
Publications
Michaelson MD, Gupta S, Agarwal N, Szmulewitz R, Powles T, Pili R, Bruce JY, Vaishampayan U, Larkin J, Rosbrook B, Wang E, Murphy D, Wang P, Lechuga MJ, Valota O, Shepard DR. A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. Oncologist. 2019 Sep;24(9):1151-e817. doi: 10.1634/theoncologist.2018-0749. Epub 2019 Jun 6.
PubMed 31171735
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A PHASE 1B, OPEN LABEL, DOSE ESCALATION STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH CRIZOTINIB (PF-02341066) IN PATIENTS WITH ADVANCED SOLID TUMORS
- ClinicalTrials.gov ID
- NCT01999972
- Acronym / sponsor ID
- A4061068
- Conditions
- Advanced Solid Tumors
- Keywords
- Carcinoma, Renal Cell
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- PfizerIndustry (pharma, biotech, devices)
- Study start
- 26 Feb 2014 (actual)
- Primary completion
- 22 Feb 2017 (actual)
- Study completion
- 5 Sep 2019 (actual)
- First posted
- 3 Dec 2013 (estimated)
- Results
- Posted 21 Jun 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment, while the majority of patients will eventually develop evasive resistance. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute to VEGF inhibitor resistance, such that combining a c-MET inhibitor with a VEGF inhibitor will provide additional clinical activity compared to VEGF inhibitor alone. This hypothesis will be tested using the cMET/ALK inhibitor, crizotinib, in combination with the VEGF inhibitor, axitinib.Since this will be the first study of axitinib given in combination with crizotinib, the study will primarily assess the safety and tolerability of the combination regimen.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Axitinib in combination with crizotinib, escalation phase | Experimental | Drug: axitinib, Drug: crizotinibDose Escalation Advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available |
| Expansion Phase Cohort 1 | Experimental | Drug: axitinib, Drug: crizotinibDose Expansion, Cohort 1: axitinib in combination with crizotinib Advanced renal cell cancer [RCC] with no prior systemic therapy |
| Expansion Phase Cohort 2 | Experimental | Drug: axitinib, Drug: crizotinibDose Expansion, Cohort 2: axitinib in combination with crizotinib Advanced renal cell cancer with at least one but no more than two prior systemic treatment regimens directed at advanced RCC |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis - Dose Escalation Phase: Histologically or cytologically confirmed diagnosis of advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available.
- Diagnosis - Dose Expansion Phase: Histologically or cytologically confirmed advanced RCC with a component of clear cell subtype
- Dose Expansion Phase: at least one measureable lesion as defined by RECIST [Response Evaluation Criterion in Solid Tumors] version 1.1.
- ECOG [Eastern Cooperative Oncology Group] Performance Status 0 or 1.
Key exclusion criteria (3 listed)
- Major surgery <4 weeks or radiation therapy <2 weeks of patient registration.
- History of or known active seizure disorder, brain metastases, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
- Dose Expansion Phase only: diagnosis of any other malignancy within 2 years prior to registration.
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 |
|---|---|---|
| axitinibAxitinib: tablets, dosage range 2 - 5 mg, given orally twice daily on a continuous dosing schedule in 28 days cycles. | Drug | Axitinib in combination with crizotinib, escalation phase |
| crizotinibCrizotinib: capsules, dosage range 200-250 mg, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle. | Drug | Axitinib in combination with crizotinib, escalation phase |
| axitinibAxitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles. | Drug | Expansion Phase Cohort 1 |
| crizotinibCrizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle. | Drug | Expansion Phase Cohort 1 |
| axitinibAxitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles. | Drug | Expansion Phase Cohort 2 |
| crizotinibCrizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle. | Drug | Expansion Phase Cohort 2 |
Primary outcome
Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
Time frame: Cycle 1 (28 days)
Toxicity as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. DLT defined as any following events attributable to any (axitinib or crizotinib) or both agents in combination: hematologic (Grade 4 neutropenia, absolute neutrophil count<1000/mm^3 with single temperature of >38.3 degrees celsius or sustained temperature of 38 degrees celsius for >1 hour; >=Grade 3 neutropenic infection; >=Grade 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia), non-hematologic (>=Grade 3 toxicities [except asymptomatic hypophosphatemia, hyperuricemia without signs, symptoms of gout, and tumor lysis syndrome], nausea, vomiting or diarrhea persisted at Grade 3 or 4 despite maximal medical therapy; Grade 3 hypertension if persistent despite anti-hypertensives); In asymptomatic participant, Grade 3 QTc prolongation (QTc>=501 msec) if persisted after correcting reversible causes, and failure to deliver >=75 percent (%) of dose of each study drug.
23 secondary outcomes
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Grade 3 or Higher Adverse Events (AEs) as Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03
Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematological Test Abnormalities
Time frame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Biochemistry Test Abnormalities
Time frame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment Visit
Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Pulse Rate at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment
Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Change From Baseline in Body Weight at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment
Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) to Worst Value
Time frame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
Number of Participants With Maximum Increase From Baseline in QTc Interval
Time frame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
Maximum Observed Plasma Concentration (Cmax) of Axitinib and Crizotinib
Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Crizotinib
Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Axitinib and Crizotinib
Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Apparent Oral Clearance (CL/F) of Axitinib and Crizotinib
Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Apparent Volume of Distribution (Vz/F) of Axitinib and Crizotinib
Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15
Percentage of Participants With Objective Response
Time frame: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
Dose Expansion Part: Duration of Response
Time frame: From first objective response until first recurrent, disease progression, or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
Dose Expansion Part: Progression-Free Survival (PFS)
Time frame: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Levels of Serum Soluble Protein Biomarkers
Time frame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Change From Baseline in Serum Concentration of Circulating microRNAs (miRNA) at End of Treatment
Time frame: Baseline, end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Percentage of c-MET Positive Tumor Cell at Baseline in Relation to Objective Response Rate (ORR)
Time frame: Baseline
Dose Expansion Part Cohort 1: Level of Plasma Soluble Protein Biomarker (c-MET)
Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 5; end of treatment (up to 35 cycles, each cycle 28 days)
Dose Expansion Part Cohort 1: Ratio of Serum Soluble Protein Biomarkers Level to Baseline Biomarkers Level by Each Timepoint
Time frame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31171735Michaelson MD, Gupta S, Agarwal N, Szmulewitz R, Powles T, Pili R, Bruce JY, Vaishampayan U, Larkin J, Rosbrook B, Wang E, Murphy D, Wang P, Lechuga MJ, Valota O, Shepard DR. A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. Oncologist. 2019 Sep;24(9):1151-e817. doi: 10.1634/theoncologist.2018-0749. Epub 2019 Jun 6.
- To obtain contact information for a study center near you, click here.Link provided by the sponsor.
- Individual participant dataSharing planned: No. Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
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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.
Pfizer CT.gov Call Center study director
Pfizer
17 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 axitinib and crizotinib in people with Advanced Solid Tumors, run by Pfizer at 17 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 4 inclusion and 3 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 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in United States, United Kingdom. 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?
Yes. Results are posted in the registry (first posted 21 Jun 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs) (time frame: Cycle 1 (28 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01999972, which also lists 1 linked publication.
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 Sep 2020.