PI-88 in Treating Patients With an Advanced Malignancy (Cancer) or Stage IV Melanoma

Cellxpert Biotechnology

Status and phase

Completed

Phase 2

Phase 1

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Melanoma (Skin)

Treatments

Drug: PI-88

Study type

Interventional

Funder types

Industry

Identifiers

NCT00073892

PROGEN-PR88201

COMIRB-01-207

CDR0000335412 (Registry Identifier)

Details and patient eligibility

About

RATIONALE: PI-88 may stop the growth of cancer by stopping blood flow to the tumor.

PURPOSE: Phase I/II trial to study the effectiveness of PI-88 in treating patients who have an advanced malignancy (cancer) or stage IV melanoma.

Full description

OBJECTIVES:

Phase I

Determine the maximum tolerated dose of PI-88 in patients with an advanced malignancy.
Determine the safety and tolerability of this drug in these patients.

Phase II

Determine the progression-free survival and time to progression in patients with stage IV melanoma treated with this drug.
Determine the biological activity of this drug in these patients.

OUTLINE: This is an open-label, dose-escalation study.

Phase I (parts 1 and 2):
- Part 1: Patients receive PI-88 subcutaneously (SC) once daily on days 1-4 and 15-18.

Cohorts of 3-6 patients receive escalating doses of PI-88 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD has been determined in part I, the effect of dose frequency is determined in patients in part II.

Part 2: Patients receive PI-88 SC once daily on days 1-4, 8-11, 15-18, and 22-25 at a dose based on the MTD determined in part 1.

Cohorts of 3 patients receive escalating doses of PI-88 until the MTD at this frequency is determined.

Phase II (patients with metastatic melanoma): Patients receive PI-88 as in phase I, part 2 at the MTD.

Treatment in both phases repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 18-69 patients (18-30 for phase I [part 1], 6-9 for phase I [part 2], and 25-30 for phase II) will be accrued for this study.

Enrollment

44 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Phase I

Histologically or cytologically confirmed malignancy
No other effective treatment available OR failed prior therapy
No prior or concurrent symptomatic or known CNS involvement or brain or meningeal metastases

Phase II

Diagnosis of stage IV melanoma
Metastatic disease must be measurable
No other effective treatment available OR failed prior therapy
Asymptomatic brain metastases allowed provided patient is off steroids

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

ECOG 0-2 OR
Karnofsky 70-100%

Life expectancy

At least 3 months

Hematopoietic

Neutrophil count greater than 1,500/mm^3
Platelet count greater than 100,000/mm^3
Negative serotonin release assay test for anti-heparin antibodies
No other abnormal bleeding tendency
No history of heparin-induced thrombocytopenia
No history of immune-mediated thrombocytopenia
No history of thrombolytic thrombocytopenic purpura
No history of other platelet disease

Hepatic

Bilirubin less than 1.5 times upper limit of normal (ULN)
AST and ALT no greater than 2 times ULN (5 times ULN if liver metastases are present)
PTT normal (20-34 sec)
PT less than 1.5 times ULN

Renal

Creatinine clearance greater than 60 mL/min OR
Glomerular filtration rate greater than 60 mL/min

Cardiovascular

No myocardial infarction within the past 3 months
No stroke within the past 3 months
No congestive heart failure within the past 3 months

Gastrointestinal

No history of acute or chronic gastrointestinal bleeding within the past 2 years
No inflammatory bowel disease

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
HIV negative
No AIDS-related illness
No serious infection within the past 4 weeks
No history of alcohol, drug, or other substance abuse
No history of allergy and/or hypersensitivity to anti-coagulants/thrombolytic agents (e.g., heparin)
No risk of bleeding due to open wounds or planned surgery
No clinically significant nonmalignant disease
No uncontrolled infection

Inclusion Criteria

Current diagnosis of metastatic melanoma, where other effective therapy was not available or had failed.
Measurable disease. Metastatic lesions had to have been measurable by MRI or CT, and cutaneous lesions by physical examination.
Biopsiable Lesion Group only: Must have had at least one biopsiable lesion that was bi-dimensionally measurable and previously unirradiated.
Age≥ 18 years.
Have voluntarily given written informed consent to participate in this study.
Performance status: ECOG 0 - 2 (Karnofsky 70 -100%).
Life expectancy of at least 3 months.
Neutrophil count > 1.5 x 109/L (1,500/mm3).
Platelet count > 100 x 109/L (100,000/mm3).
APTT normal (20 - 34 sec).
PT <1.5 x ULN.
Calculated creatinine clearance, using the Cockcroft-Gault formula, >60 mL/min. If just below 60 mL/min, then GFR>60 mL/min as determined by EDTA or DTPA scan.
Bilirubin <1.5 x ULN.
AST and ALT up to 2 x ULN; except in the presence of liver metastases; up to 5 x ULN.

Exclusion Criteria

Current symptomatic central nervous system involvement, or active brain or meningeal metastases.
Concomitant use of aspirin (> 100 mg/day), non-steroidal anti-inflammatory drugs (with the exception of COX-2 inhibitors), heparin, low molecular weight heparin or warfarin (> 1 mg/day) which was ongoing or anticipated during the study period. Low-dose aspirin (100 mg/day or less) or low-dose warfarin (1 mg/day or less) was permitted.
Heparin or low molecular weight heparin within the previous 2 weeks.
Chemotherapy, investigational therapy or hormonal therapy in the previous 4 weeks.
Radiotherapy to a major bone marrow bearing area such as pelvis, femoral heads, lumbar-sacral spine, within the previous 4 weeks. Radiotherapy to other sites within the previous 2 weeks.
History of allergy and/or hypersensitivity to anti-coagulants/thrombolytic agents, especially heparin.
History of heparin-induced thrombocytopenia, immune mediated thrombocytopenia, thrombotic thrombocytopenic purpura and/or other platelet diseases, or laboratory evidence of anti-heparin antibodies.
Myocardial infarction, stroke or congestive heart failure within the previous 3 months
History of acute or chronic gastrointestinal bleeding within the previous two years, inflammatory bowel disease, any other abnormal bleeding tendency, or patients at risk of bleeding due to open wounds or planned surgery.
Uncontrolled infection or serious infection within the previous 4 weeks.
Clinically significant non-malignant disease.
Known AIDS-related illness or HIV positive.
Women who were pregnant, breast feeding, or of childbearing potential in whom pregnancy could not be excluded.
History of abuse of alcohol, drugs or other substances.
Not recovered from major surgery if conducted prior to the study.

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

More than 4 weeks since prior chemotherapy

Endocrine therapy

More than 4 weeks since prior hormonal therapy

Radiotherapy

More than 2 weeks since prior radiotherapy
More than 4 weeks since prior radiotherapy to a major bone-marrow bearing area (e.g., pelvis, femoral heads, or lumbar-sacral spine)
Concurrent palliative radiotherapy allowed

Surgery

Recovered from prior major surgery
No concurrent surgery

Other

More than 2 weeks since prior heparin or low-molecular weight heparin
More than 4 weeks since other prior investigational therapy
No other concurrent investigational drugs
No other concurrent antineoplastic therapy
No concurrent aspirin or aspirin-containing medications
No concurrent nonsteroidal anti-inflammatory drugs
- Concurrent cyclooxygenase-2 inhibitors allowed
No concurrent heparin or low-molecular weight heparin
No concurrent warfarin or warfarin-containing medications
No other concurrent anticoagulant medications