A Study Of Crizotinib Plus VEGF Inhibitor Combinations In Patients With Advanced Solid Tumors.

NCT01441388 | Withdrawn Phase 1

• 1 other identifier: A8081030
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief 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 and exhibit disease progression while on therapy. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute significantly 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 individual VEGF inhibitors. Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib.

Conditions

Carcinoma, Renal Cell; Glioblastoma; Carcinoma, Hepatocellular

Keywords

Phase 1b; crizotinib; sunitinib; axitinib; sorafenib; bevacizumab; cMET inhibitor; VEGF inhibitor; crizotinib combination

Outcome Measures

Primary Outcomes (1)

• Dose Limiting Toxicities (DLTs).

  12 months

Secondary Outcomes (9)

• Duration of Response (DR)

  24 months

• Progression free survival (PFS)

  24 months

• Area under the plasma concentration versus time curve (AUC) of crizotinib and each VEGF inhibitor

  24 months

• Best overall response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 or , in the case of GBM (glioblastoma multiforme , RANO (Response Assessment in Neuro-Oncology) criteria.

  24 months

• Overall survival (OS) up to 12 months

  24 months

Study Arms (5)

Dose Escalation

EXPERIMENTAL

Histological or cytological diagnosis of advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available.

Drug: Crizotinib plus VEGF inhibitor combinations

Expansion Population 1

EXPERIMENTAL

Patients with histologically confirmed metastatic renal cell cancer with no prior systemic therapy directed at the malignant tumor.

Drug: Crizotinib plus axitinib; Drug: Crizotinib plus sunitinib

Expansion Population 2

EXPERIMENTAL

Patients with histologically confirmed metastatic renal cell cancer whose prior systemic therapy directed at the malignant tumor was single agent VEGF inhibitor and who now have acquired resistance to this treatment.

Drug: Crizotinib plus axitinib; Drug: Crizotinib plus sunitinib

Expansion Population 3

EXPERIMENTAL

Patients with histologically confirmed glioblastoma whose disease has failed on previous therapy, and which must have included treatment with external beam radiation and temozolomide chemotherapy, and who now have radiographically recurrent or progressive disease.

Drug: Crizotinib plus bevacizumab

Expansion Population 4

EXPERIMENTAL

Patients with histologically confirmed advanced-stage (unresectable or metastatic) hepatocellular carcinoma who have not received previous systemic therapy directed at the malignant tumor will be eligible to receive crizotinib plus sorafenib, should this combination be tested.

Drug: Crizotinib plus sorafenib

Interventions

Crizotinib plus VEGF inhibitor combinations DRUG

Three combinations will be prioritized, namely crizotinib plus axitinib, crizotinib plus sunitinib and crizotinib plus bevacizumab, with a fourth combination, crizotinib plus sorafenib to be tested only if crizotinib does not combine with either axitinib and/or sunitinib. All study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.

Dose Escalation

Crizotinib plus axitinib DRUG

Study drugs are tablets or capsules; dosage, frequency and duration to be determined.

Expansion Population 1

Crizotinib plus sunitinib DRUG

Study drugs are tablets or capsules; dosage, frequency and duration to be determined.

Expansion Population 1

Crizotinib plus bevacizumab DRUG

Study drugs are tablets or capsules except for bevacizumab which is parenteral (intravenous). Dosage, frequency and duration to be determined.

Expansion Population 3

Crizotinib plus sorafenib DRUG

Study drugs are tablets or capsules; dosage, frequency and duration to be determined.

Expansion Population 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose Escalation Population: Histological or cytological diagnosis of advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available. Lesions may be measurable or non measurable.
• Expansion Population 1: Patients with histologically confirmed metastatic renal cell cancer with no prior systemic therapy directed at the malignant tumor.
• Expansion Population 2: Patients with histologically confirmed metastatic renal cell cancer whose prior systemic therapy directed at the malignant tumor was single agent VEGF inhibitor and who now have acquired resistance to this treatment. Resistance is defined as progression following an initial response (complete or partial), or stable disease for at least 6 months on single agent VEGF inhibitor.
• Expansion Population 3: Patients with histologically confirmed glioblastoma whose disease has failed on previous therapy, and which must have included treatment with external beam radiation and temozolomide chemotherapy, and who now have radiographically recurrent or progressive disease.
• Expansion Population 4: Patients with histologically confirmed advanced-stage (unresectable or metastatic) hepatocellular carcinoma who have not received previous systemic therapy directed at the malignant tumor will be eligible to receive crizotinib plus sorafenib, should this combination be tested. Eligibility criteria also include normal hepatic function or Child-Pugh hepatic function class A.

You may not qualify if:

• Patients with hemorrhagic brain metastases or with known symptomatic brain metastases requiring steroids.
• Major surgery within 4 weeks of starting study treatment.
• Radiation therapy within 2 weeks of starting study treatment.
• Hypertension that cannot be controlled with medications (\>150/90 mmHg despite optimal medical therapy).
• For glioblastoma patients: Prior treatment of glioblastoma with Gliadel wafers, stereotactic radiation, or brachytherapy unless there is pathological or definitive radiological evidence (PET scan or perfusion MRI) of recurrent tumor or unless there is new enhancement outside of the radiation field. History of Grade 2 or greater acute intracranial hemorrhage. Radiation therapy (RT) for glioblastoma within 3 months unless there is either: a) histopathologic confirmation of recurrent tumor, or b) new enhancement on MRI outside of the RT treatment field.Concomitant treatment with therapeutic doses of anticoagulants (low dose warfarin (Coumadin) up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).

Sponsors & Collaborators

• Pfizer: lead

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Carcinoma, Renal Cell; Glioblastoma; Carcinoma, Hepatocellular

Interventions

Crizotinib; Axitinib; Sunitinib; Bevacizumab; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrroles; Indoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylurea Compounds; Urea; Niacinamide; Nicotinic Acids; Acids, Heterocyclic

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2011
• First Posted: September 27, 2011
• Study Start: December 1, 2011
• Primary Completion: November 1, 2013
• Study Completion: November 1, 2013
• Last Updated: December 20, 2011

Record last verified: 2011-12