A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential Single Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Effect of Food on Pharmacokinetics of CAL-120 in Healthy Male Subjects

The drug to be given CAL-120 is a new, investigational compound that may
eventually be used for the treatment of solid tumors. A solid tumor is an
abnormal growth of cells, with cancer of the lung, breast, colorectum, stomach
and prostate being the most common types. The large number of cancer deaths and
poor survival for many cancer types highlight the urgent need for new
therapies. The enzyme (protein) PI3K has an important role in the growth and
survival of cells. This enzyme (PI3K) can be inhibited by CAL-120, which will
inhibit the growth of the tumor. Studies in animals with tumors have shown
inhibition of solid tumors. Therefore, CAL-120 is a potential new agent for the
treatment of solid tumors.
This is the first time that this compound is being given to humans. Similar
drugs with the same method of action have been given to humans before.

In part 3 of the study, ketoconazole will also be administered. Ketoconazole is
a registered antifungal drug and is used to prevent and treat fungal skin
infections.*

Primary:
to evaluate the safety and tolerability of single dose administration of the
study drug in healthy male subjects
to determine the pharmacokinetic parameters following single dose
administration of the study drug in healthy male subjects
o evaluate the effects of CYP3A4 inhibition with ketoconazole on the PK profile
of
CAL-120 in healthy male subjects


Secundary:
to assess pharmacodynamic effects on platelet aggregation and basophil
activation , as well as the effect of food following single dose administration
of the study drug in healthy male subjects

Design:
Part 1 (single ascending dose)
- a randomized, double blind, placebo controlled, sequential single dose
escalation study with 7 groups of 8 healthy male subjects, each receiving a
single oral dose of the study drug or placebo (six verum and two placebo) as a
capsule.

Part 2 (food effects)
- A randomized, open-label, food effect study with 1 group of 12 healthy male
subjects, each receiving a single oral dose of the study drug as a capsule on
two occasions, once in a fasting state and one in a fed state.

Part 3 (drug-drug interaction)
- An open-label study with 1 group of 12 healthy male subjects, each receiving
a single oral dose of ketoconazole once per day for 5 days administered in the
fasting state. On the day of the last ketoconazole dose, the subjects will also
receive a single dose of CAL-120 administered in a fasting state.

Procedures and assessments:
Screening and follow up:
clinical laboratory, vital signs, physical examination, ECG; at eligibility
screening: medical history, height, weight, drug screen, HBsAg, anti HCV,
anti-HIV 1/2; follow-up at discharge on Day 4 (Part 1) or on Day 8 (Part 2 and
Part 3); drug screen, vital signs, haematology and clinical chemistry to be
repeated upon admission

Part 1
-Observation period:one period in clinic from -17 h up to 72 h after drug
administration on Day 1

-Blood sampling:
for pharmacokinetics of CAL-120 in plasma: pre-dose and 15, 30 min, 1, 1.5, 2,
3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose on Day 1
for pharmacodynamics of CAL-120 in blood: pre-dose and 1, 2,4, 8, 24, 48, and
72 h post-dose on Day 1
for genotyping: pre-dose on Day 1

-Urine sampling:
pharmacokinetics of CAL-120 and creatinine: pre-dose, and intervals at 0-4,
4-8, 8-12 and 12-24 post dose on Day 1.

-Safety assessments:
adverse events: throughout the study;
vital signs: pre-dose and 1, 2, 3, 4, 6, 8,12, 24, 48, and 72h post-dose on Day
1;
ECG: predose, 1, 2, 3, 4, 6 8, 12, 24, and 72h post-dose on Day 1;
telemetry: from 30 min pre-dose until 6h post-dose on Day 1.
Clinical lab (including coagulation) 24h post dose on Day 1

Part 2
-Observation period:
one period in clinic from -17 h before drug administration on Day 1 up to 72 h
after drug administration on Day 5

-Blood sampling:
for pharmacokinetics of CAL-120 in plasma: pre-dose and 15, 30 min, 1, 1.5, 2,
3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose on Days 1 and 5
for pharmacodynamics of CAL-120 in blood: pre-dose and, 2,4, 8, 24, 48, and 72
h post-dose on Days 1 and 5

-Urine sampling:
pharmacokinetics of CAL-120 and creatinine: pre-dose, and intervals at 0-4,
4-8, 8-12 and 12-24 post dose on Days 1 and 5

-Safety assessments:
adverse events: throughout the study;
vital signs: once on Days 1-8;
ECG: once on Days 1 and 8;
Clinical lab (including coagulation) 24, 72h post dose on Days 1 and 5

-Bioanalysis
analysis of plasma and urine CAL-120 samples using a validated method by PRA
whole blood FACS assay * ex vivo stimulation of basophil activation using a
validated method by PRA
whole blood FACS assay * ex vivo stimulation of platelet activation using a
validated method by PRA

Part 3:
Observation period:
one period in clinic from -17 h before drug administration on Day 1 up to 72 h
after drug administration on Day 5

Blood sampling:
for pharmacokinetics of CAL-120 in plasma: pre-dose and 15, 30 min, 1, 1.5, 2,
3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose on Day 5
for pharmacodynamics of CAL-120 in blood: pre-dose and, 2,4, 8, 24, 48, and 72
h post-dose on Day 5

Urine sampling:
pharmacokinetics of CAL-120 and creatinine: pre-dose, and intervals at 0-4,
4-8, 8-12 and 12-24 post dose on Day 5

Safety assessments:
adverse events: throughout the study; vital signs: once on Days 1-8; ECG: once
on Days 5 and 8; clinical lab (including coagulation) 24, 72h post dose on Day
5

Bioanalysis:
analysis of plasma and urine CAL-120 samples using a validated method by PRA
whole blood FACS assay * ex vivo stimulation of basophil activation using a
validated method by PRA
whole blood FACS assay * ex vivo stimulation of platelet activation using a
validated method by PRA

Active substance: CAL-120
Activity: PI3-kinase inhibitor
Dosage form: capsule

Active substance: Ketoconazol
Activity: CYP3A4 inhibitor
Dosage form: tablet

Procedures: pain, light bleeding, heamatoma, possibly an infection.