An Open-label Phase II Study Evaluating the Safety and Efficacy of PTK787/ZK222584 in Patients With Metastatic Neuroendocrine Tumors That Have Evidence of Progressive Disease or an Increase in Disease Related Syndrome Symptoms.
This is an open-label, phase II study evaluating the safety and efficacy of PTK787/ZK222584
administered daily in subjects with neuroendocrine tumors that are experiencing progressive
disease and/or whose tumor-related syndrome symptoms (flushing and diarrhea) are considered
inadequately controlled despite optimal doses of octreotide therapy. Inadequate control is
defined as a minimum of 2 flushing episodes or 6 bowel movements per day for 7 consecutive
days. Subjects who meet all inclusion and exclusion criteria and have completed all baseline
and screening testing will receive an initial dose of PTK787/ZK222584 1,250 mg once daily
and subjects will also remain on the scheduled doses of Sandostatin LAR 30 mg every 4 weeks.
Both drugs will be dosed on a flat schedule of mg, not by weight or body surface area. The
PTK787/ZK222584 medication will be taken orally with daily dosing. Each tablet of PTK787/ZK
222584 is 250 mg. The subject will take five tablets of study medication per day 2 tabs am
and 3 tabs pm. Subjects may continue to receive therapy as long as they do not experience
unacceptable toxicities or evidence of disease progression as defined by RECIST criteria.
Subjects will be evaluated with a daily log to assess the degree of symptom control
(flushing and diarrhea) and subjects will be monitored every 2 weeks for 3 months then
monthly for biochemical control and every three months for tumor response. Subjects will be
monitored by the Investigator every two weeks for 3 months then monthly for safety and
- Biopsy-proven metastatic neuroendocrine tumors (which extent is disease is determined
by CT scan or MRI) and biochemical evidence of disease.
- Evidence of progressive disease or inadequate controlled disease related syndrome
- Must be receiving Sandostatin LAR 30mg every 4 weeks
- Age >or= to 18 years old
- Karnofsky Performance Status > or = 60
- Measurable lesion(s) as per the modified RECIST criteria
- Laboratory values or= 1.5 x 10(9)/L,
Platelets >or= 100 x 10 (9), Hemoglobin >or= 9g/dL, Serum creatinine
present), Negative for proteinuria based on dip stick reading OR documentation of 1+
result for protein on dip stick reading, then total urinary protein
measured creatinine clearance >or= 50ml/min from a 24 hour urine collection.
- Life expectancy >or= 12 weeks.
- Written informed consent obtained according to local guidelines.
- Had previous radiolabeled somatostatin analog therapy within the last 6 months.
- Hepatic artery embolization within the last 6 months (1 month if there are other
sites of measurable disease)
- Undergone cryoablation of hepatic metastasis within the last 2 months.
- History or presence of central nervous system (CNS) disease (ie:primary brain tumor,
malignant seizures, CNS metastases or carcinomatous meningitis)
- History of another primary malignancy
basal or squamous cell carcinoma of the skin.
- Prior chemotherapy
must have recovered from all therapy-related toxicities.
- Prior biologic or immunotherapy
randomization. Patients must have recovered from all therapy-related toxicities.
- Prior full field radiotherapy
prior to randomization. Patients must have recovered from all therapy-related
toxicities. The site of previous radiotherapy should have evidence of progressive
disease if this is the only site of disease.
- Major surgery (ie:laparotomy)
2 weeks prior to randomization. Insertion of a vascular access device is not
considered major or minor surgery in this regard. Patients must have recovered from
all surgery-related toxicities.
- Patients who have received investigational drugs
- Prior therapy with anti-VEGF agents
- Pleural effusion or ascites that causes respiratory compromise (>or= CTC grade 2
- Female patients who are pregnant or breast feeding or adults of reproductive
potential not employing an effective method of birth control. Barrier contraceptives
must be used throughout the trial in both sexes. Oral, implantable, or injectable
contraceptives may be affected by cytochrome P450 interactions, therefore not
considered effective for this study. Women of childbearing potential must have a
negative serum pregnancy test 48 hours prior to administration of study treatment.
- Uncontrolled high blood pressure, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen.
- Unstable angina pectoris
- Symptomatic congestive heart failure
- Myocardial infarction
- Active or uncontrolled infection
- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
- Chronic renal disease
- Subjects at risk of significant cardiac arrythmias
- Uncontrolled diabetes
- Acute or chronic liver disease (eg:hepatitis, cirrhosis)
- Impairment of gastrointestinal function or GI disease that may significantly alter
absorption (ie:ulcerative disease, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, bowel obstruction, or inability to swallow the tablets.)
- Confirmed diagnosis of human immunodeficiency syndrome (HIV) infection are excluded
at the investigator's discretion.
- Patients taking therapeutic warfarin sodium (Coumadin) or similar oral anticoagulants
that are metabolized by the cytochrome P450 system. Heparin is allowed.
- Patients unwilling or unable to comply with the protocol.
- Known symptomatic gallstones
- Received glucocorticoid therapy within the past 6 months, or who are currently
receiving any chemotherapeutic agents, insulin sensitizers (eg:metformin,
pioglitazone, rosiglitazone), or exogenous growth hormones.
- Subjects with unacceptable concomitant diagnoses, or who have received medication
and/or therapies (ie:illness or therapies that would place patient at increased risk,
or would, in the opinion of the investigator, interfere with the evaluation of
efficacy or safety.)
- Exhibit symptoms indicative of intolerance of Sandostatin LAR.
Type of Study:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Change in biochemical markers.
Outcome Time Frame:
Quarterly= every 3 months
Lowell B Anthony, MD
Lousiana State University Health Sciences Center-NO
United States: Food and Drug Administration
- Metastatic Neuroendocrine Tumors
- Neuroendocrine Tumors
||Kenner, Louisiana 70065