Pazopanib or Pemetrexed and Crizotinib in Advanced Cancer
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| ClinicalTrials.gov Identifier: NCT01548144 |
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Recruitment Status :
Terminated
(PI request)
First Posted : March 8, 2012
Last Update Posted : September 13, 2021
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The goal of this clinical research study is to find the highest tolerable dose of the combination of Xalkori (crizotinib) either with Votrient (pazopanib) or Alimta (pemetrexed) or of the combination of 3 study drugs that can be given to patients with advanced cancer. The safety of these drug combinations will also be studied.
Crizotinib is designed to block a protein called ALK, which is involved in cancer cell growth and survival.
Pazopanib is designed to block the growth of blood vessels that supply nutrients needed for tumor growth. This may prevent or slow the growth of cancer cells.
Pemetrexed is designed to block proteins that may cause tumors to grow.
This is an investigational study. Crizotinib is FDA approved and commercially available for the treatment of locally advanced or metastatic non-small cell lung cancer. Pazopanib is FDA approved and commercially available for treatment of advanced renal cell carcinoma. Pemetrexed is FDA approved and commercially available for the treatment of non-small cell lung cancer.
The combination of crizotinib with pazopanib, crizotinib with pemetrexed, pazopanib with pemetrexed, and giving all 3 drugs together to patients with advanced cancer is investigational.
Up to 364 patients will take part in this study. All will be enrolled at MD Anderson.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Advanced Cancers | Drug: Crizotinib (Xalkori) Drug: Pazopanib Drug: Pemetrexed | Phase 1 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 178 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Two Steps Phase I Trial of Pazopanib or Pemetrexed in Combination With Crizotinib Followed by the Triplet, Crizotinib Plus Pazopanib Plus Pemetrexed in Patients With Advanced Malignancies |
| Actual Study Start Date : | April 2012 |
| Actual Primary Completion Date : | August 26, 2021 |
| Actual Study Completion Date : | August 26, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Crizotinib + Pazopanib - Group A
Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Dose Expansion Group: MTD from Phase 1. Starting Dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle. Dose Expansion Group: MTD from Phase 1. |
Drug: Crizotinib (Xalkori)
Starting dose for Crizotinib - Groups A, B, C: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Expansion Groups Starting Dose: MTD from Phase 1. Other Names:
Drug: Pazopanib Starting Dose for Pazopanib - Groups A, C, D: 200 mg by mouth daily in a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Other Name: GW786034 |
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Experimental: Crizotinib + Pemetrexed - Group B
Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Dose Expansion Group: MTD from Phase 1. Starting dose for Pemetrexed: 200 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle. Dose Expansion Group: MTD from Phase 1. |
Drug: Crizotinib (Xalkori)
Starting dose for Crizotinib - Groups A, B, C: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Expansion Groups Starting Dose: MTD from Phase 1. Other Names:
Drug: Pemetrexed Starting dose for Pemetrexed - Groups B + C: 200 mg/m2 by vein on Day 1 of a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Starting dose for Pemetrexed Group D: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle. Expansion Group Starting Dose: MTD from Phase 1. Other Names:
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Experimental: Pazopanib + Pemetrexed - Group C
Starting dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle. Expansion group starting dose: MTD from Phase 1. Starting dose for Pemetrexed: 200 mg/m2 by vein on Day 1 of a 21 day cycle. Expansion group starting dose: MTD from Phase 1. |
Drug: Pazopanib
Starting Dose for Pazopanib - Groups A, C, D: 200 mg by mouth daily in a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Other Name: GW786034 Drug: Pemetrexed Starting dose for Pemetrexed - Groups B + C: 200 mg/m2 by vein on Day 1 of a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Starting dose for Pemetrexed Group D: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle. Expansion Group Starting Dose: MTD from Phase 1. Other Names:
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Experimental: Crizotinib + Pazopanib + Pemetrexed - Group D
Starting dose for Crizotinib: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Dose Expansion Group: MTD from Phase 1. Starting Dose for Pazopanib: 200 mg by mouth daily in a 21 day cycle. Dose Expansion Group: MTD from Phase 1. Starting dose for Pemetrexed: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle. Dose Expansion Group: MTD from Phase 1. |
Drug: Crizotinib (Xalkori)
Starting dose for Crizotinib - Groups A, B, C: 250 mg by mouth every other day, 1 or 2 times a day on Day 1 of a 21 day cycle. Participant told how often to take this drug. Expansion Groups Starting Dose: MTD from Phase 1. Other Names:
Drug: Pazopanib Starting Dose for Pazopanib - Groups A, C, D: 200 mg by mouth daily in a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Other Name: GW786034 Drug: Pemetrexed Starting dose for Pemetrexed - Groups B + C: 200 mg/m2 by vein on Day 1 of a 21 day cycle. Expansion Groups Starting Dose: MTD from Phase 1. Starting dose for Pemetrexed Group D: 400 mg/m2 by vein every 3 weeks on Day 1 of a 21 day cycle. Expansion Group Starting Dose: MTD from Phase 1. Other Names:
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- Maximum Tolerated Dose (MTD) of Crizotinib and Pazopanib [ Time Frame: 4 weeks ]If not more than 33% of participants in cohort develop dose limiting toxicity (DLT), this cohort considered MTD. MTD defined by DLTs that occur in first cycle (4 weeks). DLT defined as: Clinically grade 3 or 4 non-hematologic toxicity. Grade 4 hematologic toxicity lasting 3 weeks or longer. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens. Grade 3 non-hematologic toxicity including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in the NCI-CTCAE v4.0 attributable to therapy.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with advanced cancer, either refractory to standard therapy or for which no effective standard therapy that increases survival for at least 3 months is available.
- Patients must have measurable or evaluable disease, as defined by RECIST 1.1.
- Women of child-bearing potential and men must agree to use adequate contraception.
- ECOG performance status of 0 to 2.
- Adequate organ functions: (Crizotinib plus Pazopanib arm A): Neutrophils > 1000/uL; Platelets ≥ 75,000/uL; Total bilirubin < or= 2 x ULN (upper limit of normal); ALT < or = 2.5 x ULN or < o r= 5 x ULN if liver metastases persist; Serum creatinine < 2 x ULN (Crizotinib plus Pemetrexed arm B, Pazopanib plus Pemetrexed arm C, Crizotinib plus Pazopanib plus Pemetrexed arm D) Neutrophils > 1500/uL; Platelets > or = 100,000/uL; Total bilirubin < or = 2 x ULN (upper limit of normal); ALT < or = 2.5 x ULN or < or = 5 x ULN if liver metastases persist; Calculated GFR > 45 mL/min.
- Creatinine Clearance: The standard Cockcroft and Gault formula must be used to calculate CrCl for enrollment or dosing. Also include in the pre-treatment or baseline text portion of the protocol, the 'On Study Evaluations or During Treatment' for every Pemetrexed treatment day, and also capture in the study Schedule of Events. No dosage adjustment is needed in patients with creatinine clearance > 45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, Pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min.
- For pemetrexed arms: The ability to interrupt NSAIDs 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.
- The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol for all pemetrexed arms.
- Expansion cohort only for arms containing crizotinib: arm A (Crizotinib plus Pazopanib) and arm B (Crizotinib plus Pemetrexed) and arm D (Crizotinib plus Pazopanib Plus Pemetrexed) but not arm C (Pazopanib plus Pemetrexed). Patients must have ALK abnormality including: translocation, ALK amplification, mutation and overexpression as determined by FISH, IHC, qPCR, qRT-PCR, array Comparative Genomic Hybridization or direct sequencing (aCGH). Or patients must have a c-Met abnormality; either c-Met amplification or c-Met mutation or patients must have the ROS1 translocation as determined by FISH.
Exclusion Criteria:
- Patient receiving any concurrent chemotherapy.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics.
- Symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris or congenital long QT syndrome.
- Medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk.
- Known anaphylactic or severe hypersensitivity to study drugs or their analogs.
- Patient has failed to recover from any prior surgery within 4 weeks of study entry.
- Patient is pregnant or lactating.
- Patient has had any treatment specific for tumor control within 3 weeks of dosing with investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of biological targeted agents with half-lives and pharmacodynamic effects lasting less than 5 days (that includes, but is not limited to, erlotinib, sorafenib, sunitinib, bortezomib, and other similar agents).
- Patient has any signs of intestinal obstruction.
- Patient is not able to swallow oral medication.
- Patients receiving whole brain radiation within 14 days prior to the first dose of study drugs will be excluded. NOTE: Patients receiving palliative radiation (other than whole brain) before or during treatment may still be eligible as long as there are evaluable lesions that are not being irradiated.
- Pemetrexed arms only: Presence of third space fluid which cannot be controlled by drainage.
- Additional Exclusions for the 3 pazopanib containing arms (Crizotinib plus Pazopanib) and (Pazopanib plus Pemetrexed) and (Crizotinib plus Pazopanib plus Pemetrexed). 1. History of stroke or transient ischemic attack within 6 months prior to study enrollment. 2. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment. 3. Urine for proteinuria > or = 2+ (patients discovered to have > or = 2+ proteinuria on urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate < or = 1g of protein in 24 hours to be eligible).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01548144
| United States, Texas | |
| University of Texas MD Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Sarina Piha-Paul, MD | M.D. Anderson Cancer Center |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT01548144 |
| Other Study ID Numbers: |
2011-1142 NCI-2012-00324 ( Registry Identifier: NCI CTRP ) |
| First Posted: | March 8, 2012 Key Record Dates |
| Last Update Posted: | September 13, 2021 |
| Last Verified: | September 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Crizotinib PF-02341066 Pazopanib Gw786034 Pemetrexed Alimta |
Multitargeted Antifolate Advanced Cancers Advanced Malignancies LY231514 MTA NSC-698037 |
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Neoplasms Pemetrexed Crizotinib Antineoplastic Agents Enzyme Inhibitors |
Molecular Mechanisms of Pharmacological Action Folic Acid Antagonists Nucleic Acid Synthesis Inhibitors Protein Kinase Inhibitors |