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

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, GCP and applicable regulatory requirements.

Inclusion Criteria:

1. Voluntary written informed consent of the subject obtained before any study-specific
procedure.

2. Histologically or cytologically confirmed malignant solid tumor or lymphoma.

3. Subjects with malignancies that are not otherwise curable or for which no effective
standard therapy exists.

4. Age ≥ 18 years.

5. Subject with measurable or non-measurable disease using the RECIST criteria

6. Recovery from any drug-related adverse event related to previous treatment, excluding
alopecia and NCI-CTCAE grade < 2 peripheral neuropathy.

7. 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 tromboplastin within normal limits for the institution

- INR within normal limits for the institution (unless due to oral anticoagulation)

8. Performance status (ECOG) ≤ 1

9. Life expectancy ≥ 3 months.

10. Left ventricular ejection fraction (LVEF) within normal limits for the institution
(LVEF of at least 50%).

11. 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, IUD,
oral contraceptive, subdermal implant and double barrier (condom with a contraceptive
sponge or contraceptive suppository).

Exclusion Criteria:

1. Prior therapy with PM00104

2. Pregnant or lactating women.

3. 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).

4. Prior high dose chemotherapy that needed bone marrow transplant support.

5. Subjects with untreated or uncontrolled brain or meningeal metastases.

6. 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-QTc > 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.

7. 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.

8. Treatment with any investigational product in the 30 days period prior to the first
infusion.

9. Known hypersensitivity to any of the components of the drug product, including sucrose
or potassium phosphate.