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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


Phase 1
N/A
N/A
Open (Enrolling)
Both
Advanced Cancers

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Trial Information

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


Study groups:

Dose escalation:

If you are found to be eligible to take part in this study, your doctor will decide if you
will receive one of the following drug combinations:

- If you are in Group A, you will receive crizotinib and pazopanib.

- If you are in Group B, you will receive crizotinib and pemetrexed.

- If you are in Group C, you will receive pazopanib and pemetrexed.

- If you are in Group D, you will receive crizotinib, pazopanib, and pemetrexed.

Once it is decided which combination you will receive, you will be assigned to a dose level
based on when you join the study.

Up to 8 dose levels of crizotinib with pazopanib will be tested. Up to 6 dose levels of
crizotinib with pemetrexed will be tested. Up to 6 dose levels of pazopanib with pemetrexed
will be tested. Up to 8 dose levels of pazopanib with pemetrexed and crizotinib will be
tested. Up to 6 participants will be enrolled at each dose level.

The first group of participants will receive the lowest dose level. Each new group will
receive a higher dose than the group before it, if no intolerable side effects were seen.
This will continue until the highest tolerable dose combination is found.

Dose expansion:

Once the highest tolerable dose of each study drug combination is found, up to 14 more
participants may be enrolled to further study the safety of each combination of drugs at
that dose.

Study Drug Administration:

Each study cycle is 21 days. Drugs should be taken and/or administered simultaneously. On
days of pharmacokinetic testing (if you agree) you should take the drugs at least 1 hour
before or 2 hours after a meal.

If you are taking crizotinib, you will take it by mouth at the same time every day
consistently either with or without food. It should be swallowed whole with a glass of
water. You will take the drug every other day, 1 or 2 times a day. You will be told how
often to take this drug.

If you are taking pazopanib, you will take it by mouth at the same time every day with a
glass of water. You should take it at least 1 hour before or 2 hours after a meal.

If you receive pemetrexed:

- You will receive it by vein on Day 1 of each cycle over about 10 minutes.

- About 7 days before your first dose of pemetrexed, you will start taking folic acid to
help lower the risk of side effects. Although the study drug is designed to prevent
the body from making folic acid that could help cancer grow and spread, some folic acid
is needed to prevent side effects in non-cancerous tissue. You will take folic acid by
mouth 1 time every day until at least 30 days after you received the last dose of
pemetrexed.

- At least 7 days before your first dose of pemetrexed, you will receive a vitamin B12
injection. You will receive an injection of Vitamin B12 about every 9 weeks after that.
Vitamin B12 is given to help reduce the risks of side effects.

- You will take dexamethasone by mouth 2 times a day on the day before, the day of, and
the day after you receive pemetrexed.

Study Visits:

At every study visit, you will be asked about any other drugs or herbal supplements you are
taking and about any side effects you may have.

During Cycles 1 and 2, you will have weekly blood (about 1 tablespoon) collected for routine
tests.

During Week 1 of Cycles 2 and beyond:

- Your medical history will be recorded, including any cancer symptoms.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- Blood (about 1 tablespoon) and urine will be collected for routine tests.

- Blood (about 1 tablespoon) will be drawn for tumor marker testing.

- If your doctor thinks it is needed, you will have an ECG to check your heart function.

After about 6 weeks and then every 2-3 cycles after that, you will have a CT scan, x-ray,
MRI scan, and/or PET scan to check the status of the disease. It may be done more often if
your study doctor thinks it is needed.

If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test every 2 cycles or at any time the study doctor thinks it is needed.

Length of Study Participation:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-dosing
and/or follow-up visits.

End-of-Dosing Visit:

Within 30 days after your last dose of study drugs, you will have an end-of-study visit. If
you are having side effects at the time of this visit, you may have follow-up for a longer
period of time. At this visit, the following tests or procedures may be performed:

- Your medical history will be recorded, including any cancer symptoms.

- You will be asked if you have had any side effects.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- Blood (about 1 tablespoon) and urine will be collected for routine tests.

- Blood (about 1 tablespoon) will be drawn for tumor marker testing.

- If the doctor thinks it is needed, you will have an x-ray, CT scan, MRI scan, and/or
PET/CT scan to check the status of the disease.

- If your doctor thinks it is needed, you will have an ECG to check your heart function.

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.


Inclusion Criteria:



1. 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.

2. Patients must have measurable or evaluable disease, as defined by RECIST 1.1.

3. Women of child-bearing potential and men must agree to use adequate contraception.

4. ECOG performance status of 0 to 2.

5. 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.

6. 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.

7. 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.

8. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol
for all pemetrexed arms.

9. 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:

1. Patient receiving any concurrent chemotherapy.

2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics.

3. Symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris
or congenital long QT syndrome.

4. Medical and/or psychiatric problems of sufficient severity to limit full compliance
with the study or expose patients to undue risk.

5. Known anaphylactic or severe hypersensitivity to study drugs or their analogs.

6. Patient has failed to recover from any prior surgery within 4 weeks of study entry.

7. Patient is pregnant or lactating.

8. 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).

9. Patient has any signs of intestinal obstruction.

10. Patient is not able to swallow oral medication.

11. 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.

12. Pemetrexed arms only: Presence of third space fluid which cannot be controlled by
drainage.

13. 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).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

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.

Outcome Time Frame:

4 weeks

Safety Issue:

No

Principal Investigator

Ralph Zinner, MD,BA

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2011-1142

NCT ID:

NCT01548144

Start Date:

April 2012

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Advanced Cancers
  • Advanced Malignancies
  • Crizotinib
  • PF-02341066
  • Pazopanib
  • Gw786034
  • Pemetrexed
  • LY231514
  • Alimta
  • MTA
  • Multitargeted Antifolate
  • NSC-698037
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030