A Phase I Study of Zalypsis (PM00104) in Subjects With Advanced Malignant Solid Tumors or Lymphoma

Phase 1

Terminated

Conditions: Solid Tumors
Lymphoma

Interventions: Drug: PM00104

Registration Number: NCT00359294

Lead Sponsor: PharmaMar

Brief Summary: Phase I trial, dose escalating, prospective, open-label, non-randomized, multicenter study. The purpose is to determine the safety, tolerability, dose limiting toxicity (DLT) and recommended dose (RD) of PM00104, administered intravenously over 1 hour daily for 5 days every 3 weeks (this is considered as 1 cycle) to subjects with advanced malignant solid tumors or lymphoma.

Detailed Description: Phase I trial, dose escalating, prospective, open-label, non-randomized, multicenter study. The purpose is to determine the safety, tolerability, dose limiting toxicity (DLT) and recommended dose (RD) of PM00104, administered intravenously over 1 hour daily for 5 days every 3 weeks (this is considered as 1 cycle) to subjects with advanced malignant solid tumors or lymphoma. Secondary objectives are to determine the preliminary pharmacokinetics of PM00104, to evaluate the relationship between pharmacokinetics/pharmacodynamics and to evaluate the preliminary antitumor activity of PM00104. Dose-escalation guidelines will follow an accelerated phase I design for conventional cytotoxic agents in order to minimize the number of subjects treated at the subtoxic dose levels. The trial will be conducted in compliance with the protocol, Good clinical practice (GCP) and applicable regulatory requirements.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Voluntary written informed consent of the subject obtained before any study-specific procedure.
Histologically or cytologically confirmed malignant solid tumor or lymphoma.
Subjects with malignancies that are not otherwise curable or for which no effective standard therapy exists.
Age ≥ 18 years.
Subject with measurable or non-measurable disease using the RECIST criteria
Recovery from any drug-related adverse event related to previous treatment, excluding alopecia and NCI-CTCAE grade < 2 peripheral neuropathy.
Laboratory values within 7 days prior to first infusion:
- Platelet count ≥ 100 x109/L, hemoglobin ≥ 9 g/dL and absolute neutrophil count (ANC) ≥ 1.5 x109/L.
- Alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN) (≤ 5 x ULN in case of extensive bone metastases)
- Aspartate aminotransferase (AST): ≤ 2.5 x ULN
- Alanine aminotransferase (ALT): ≤ 2.5 x ULN
- Total bilirubin: ≤ 1.5 ULN, unless due to Gilbert's syndrome.
- Creatinine: ≤ ULN, or calculated creatinine clearance: ≥ 60 mL/min (calculated from the Cockcroft-Gault formula; see Appendix III).
- Albumin: ≥ 2.5 g/dL.
- Partial thromboplastin within normal limits for the institution
- International normalized ratio (INR) within normal limits for the institution (unless due to oral anticoagulation)
Performance status (ECOG) ≤ 1
Life expectancy ≥ 3 months.
Left ventricular ejection fraction (LVEF) within normal limits for the institution (LVEF of at least 50%).
Women of childbearing potential must have a negative serum pregnancy test before study entry. Both men and women must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment. Acceptable methods of contraception include complete abstinence, Intrauterine device, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive suppository).

Exclusion Criteria

Prior therapy with PM00104
Pregnant or lactating women.
Less than 4 weeks from radiation therapy (8 weeks in case of extensive prior radiotherapy) or last dose of hormonal therapy, biological therapy or chemotherapy (6 weeks in case of nitrosourea, mitomycin C).
Prior high dose chemotherapy that needed bone marrow transplant support.
Subjects with untreated or uncontrolled brain or meningeal metastases.
Other relevant diseases or adverse clinical conditions:
- Increased cardiac risk as defined by:
  - History or presence of unstable angina.
  - History or presence of myocardial infarction.
  - Congestive heart failure.
  - Symptomatic arrhythmia or any arrhythmia requiring ongoing treatment.
  - Abnormal ECG (i.e., patients with the following are excluded: QT prolongation-corrected QT interval > 480 msec-, signs of cardiac enlargement or hypertrophy, bundle branch block, partial bundle branch blocks, signs of ischemia or necrosis, Wolff-Parkinson-White patterns).
  - History or presence of valvular heart disease.
  - Uncontrolled arterial hypertension despite optimal medical therapy.
  - Previous mediastinal radiotherapy.
  - Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m2
- History of significant neurological or psychiatric disorders.
- Active infection.
- Significant non-neoplastic liver disease (e.g., cirrhosis, chronic active hepatitis).
- Significant non-neoplastic renal disease.
- Immunocompromised subjects, including subjects known to be infected by human immunodeficiency virus (HIV).
- Uncontrolled endocrine diseases (e.g., diabetes mellitus, hypothyroidism or hyperthyroidism, adrenal disorder) requiring relevant changes in medication within the last month or hospital admission within the last 3 months.
- Any other major illness that, in the investigator's judgment, could substantially increase the risk associated with the subject's participation in this study.
Limitation of the subject's ability to comply with the treatment or to follow-up at a participating center. Subjects registered on this trial must be treated and followed at a participating center.
Treatment with any investigational product in the 30 days period prior to the first infusion.
Known hypersensitivity to any of the components of the drug product, including sucrose or potassium phosphate.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Zalypsis (PM00104)	PM00104	-

Primary Outcome Measures

Name	Time	Method
Patients With Dose Limiting Toxicities (DLT)	During the first cycle (21 days)	DLTs were defined as follows: * Hematological adverse events: * Any grade 4 neutropenia (absolute neutrophil count (ANC) \< 0.5 x109/l) for longer than five days; * Any grade 4 neutropenia accompanied by fever (at least 38.5°C); * Any grade 4 neutropenia and sepsis or other severe infection; * Any grade 4 thrombocytopenia. * Any other grade 3/4 non-hematological adverse event (AE) and any increase of cardiac troponin I ≥0.1 ng/ml together with evidence of cardiac damage by electrocardiogram (ECG) or echocardiogram (ECHO), except for untreated nausea/vomiting or hypersensitivity reactions. * Decrease in left ventricular ejection fraction (LVEF) \> 20% compared to the patient's baseline value and/or LVEF \< 50% below normal limits for the institution. * Delay in the initiation of a subsequent dose exceeding two weeks due to drug related AEs

Secondary Outcome Measures

Name	Time	Method
Overall Best Tumor Response	every six weeks while on study, up to 2 years	Best tumor response was defined as the best response achieved during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response (CR): disappearance of all lesions; Partial response (PR): ≥10% decrease in target lesion size or ≥15% decrease in tumor density; Disease progression (PD): ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; Stable disease (SD): none of the CR, PR, or PD criteria met; RECIST,

Trial Locations

Locations (2): Massachusetts General Hospital
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Boston, Massachusetts, United States
Fox Chase Cancer Center
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Philadelphia, Pennsylvania, United States