[Lyn]

Hi there, this is what info I have so far, starting with the e-mail, my appointment is on December 22nd. I have to send it in 2 parts, apparently too long.

Love & Hugs Lyn

Hi Boris,

This is to follow up on my telephone call yesterday about the phase I study (see attached file). The CYT997 agent was developed by Cytopia, a Melbourne-based biotechnology company, and the first-in-human study is being done at the RBWH and Q-Pharm. It showed impressive anti-cancer activity in preclinical studies and appears to be both a cytotoxic and vascular-targeted agent. So far, we have treated 8 patients (the last two at dose-level 3) without any definite toxicity. One patient developed ischaemic chest pain and a small troponin rise 2 days after completing their 6th CYT997 dose (on dose-level 2). We flagged this SAE as possibily related to CYT997, given the vascular-targeting activity of the agent; however, the patient has diabetes and hypertension, which are more likely etiologies. They have made a good recovery. There have been no other toxicities. We have had patients with stable disease for up to 6 cycles, but no objective responses as yet. However, it is likely that we may not have reached a biologically-effective dose level yet.

Patients need to have a good performance status and be willing to undergo the study visits and investigations. They should have a solid tumour with no further standard therapeutic options available.

For referrals, I can be contacted through the RBWH switch (3636-8111) or our research coordinator Annette Cubitt can be reached on 3636-7712.

Best regards,

Jason.
CYT997 Protocol Synopsis



Title:Phase I dose-escalation study of CYT997 given as a 24-hour intravenous infusion every three weeks in patients with advanced solid tumours



Background and Rationale

CYT997 is a novel cytotoxic and vascular-targeting agent with activity in preclinical models of solid tumours and leukemia. The compound interferes with microtubule assembly, causing cancer cells to accumulate in the G2/M phase of the cell cycle and subsequently undergo apoptosis. In addition, CYT997 disrupts neoplastic microvasculature and reduces tumour blood flow. The doses required for anti-cancer effects were well tolerated by tumour-bearing mice and toxicology studies in rats and dogs have now confirmed the feasibility of a dose-finding study in patients with advanced cancer.



Objectives



Primary objective:

To establish the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of CYT997 given as a 24-hour continuous IV infusion



Secondary objectives:

(i) To study the pharmacokinetics of CYT997

(ii) To characterize the toxicities and tolerability of CYT997

(iii) To define a recommended dose for phase II studies

(iv) To make a preliminary evaluation of anti-tumour activity

(v) To make a preliminary evaluation of vascular-targeting activity

(vi) To assess for pharmacokinetic/pharmacodynamic (PK/PD) relationships



Study Design: Single-agent phase I and pharmacokinetic dose-escalation clinical trial



Inclusion Criteria



1. Patients must have histologically confirmed solid malignancy (including lymphoma) that is metastatic or unresectable and for which standard curative or palliative anti-neoplastic treatments do not exist or are no longer effective.



2. No anti-cancer chemotherapy or hormonal therapy for at least 4 weeks (6 weeks if the last regimen included BCNU, CCNU or mitomycin-C).



3. Age ³ 18 years.



4. ECOG performance status £ 2



5. Life expectancy of greater than 3 months.



6. Patients must have adequate organ and marrow function as defined below:

· Absolute neutrophil count ³ 1.5 ´ 109/L

· Platelet count ³ 100 ´ 109/L

· Total bilirubin ≤ 1.5 ´ upper limit of normal (ULN)

· AST and ALT ≤ 3 ´ ULN (≤ 5 ´ ULN if documented liver metastases)

· Creatinine ≤ 1.5 ´ ULN

· Normal left ventricular ejection fraction on a gated blood pool scan or echocardiogram



7. The effects of CYT997 on the human reproductive system and developing human foetus are unknown. Therefore, women of child-bearing potential and their male partners must agree to use an effective barrier method of contraception prior to study entry, for the duration of study participation and for 1 month following the completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.



8. Ability to understand and the willingness to sign a written informed consent document.



Exclusion Criteria



1. Patients may not have received any other investigational agents in the last 4 weeks prior to the start of treatment.



2. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.



3. Because CYT997 may have vascular targeting activity, patients with the following conditions will be excluded:

- Myocardial infarction or stroke within 6 months

- Unstable angina pectoris or acute ischemic changes on ECG

- History of diabetic retinopathy

- Symptomatic peripheral arterial disease

- Major surgery in the last 30 days



4. Gastrointestinal toxicity was the DLT in animal toxicology studies of CYT997. Therefore, patients with uncontrolled diarrhoea despite optimal medication and those with any history of acute gastrointestinal bleeding will be excluded.



5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.



6. Pregnant women are excluded from this study because CYT997 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued if the mother is treated with CYT997.



7. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients are excluded from the study.



Interventions

Each dose of CYT997 will be administered as a 24-hour continuous IV infusion, with one dose per cycle and cycles repeated every 3 weeks. The starting dose will be 7 mg/m2, which is one tenth of the severely toxic dose 10% in animals. Dose escalation will proceed according to a modified Fibonacci series, as shown in the table below. In the absence of major toxicities, 3 patients will be enrolled at each dose level. Once a DLT occurs, a total of 6 patients will be treated at that dose level. Continued dose escalation will be permitted if no further DLTs are observed among these 6 patients; however, if two DLTs are observed in this cohort, it will be assumed that the MTD has been reached.



DLT is defined by any of the following:

· Grade 4 neutropenia lasting ³ 5 days or associated with fever (³38.5°C) requiring antibiotics

· Grade 4 thrombocytopenia (grade 3 in the setting of bleeding)

· Non-hematological toxicity ³ grade 3 (excluding nausea, vomiting and diarrhea, unless receiving optimal supportive care)

Dose Escalation Schedule

Dose Level

Dose of CYT997

Level 1

7 mg/m2

Level 2

14 mg/m2

Level 3

23 mg/m2

Level 4

35 mg/m2

Level 5

49 mg/m2

Level 6 and above

Dose = 1.33 ´ previous dose level

Treatment with CYT997 will continue until disease progression or development of unacceptable toxicity. Escalation of the dose to that of the cohort above may occur if there are no DLTs in the cohort above.



Pharmacokinetic Evaluations

Levels of CYT997 in blood and urine will be determined for the first dose of drug in all patients.



Safety Monitoring

Patients will be admitted to the Q-Pharm phase I facility for each 24-hour CYT997 infusion. Following the first dose, patients will remain as inpatients at Q-Pharm for a further 24 hours to permit intensive safety monitoring and collection of pharmacokinetic samples. In subsequent cycles of treatment, patients may be discharged from the Q-Pharm facility after completion of the CYT997 infusion. The following safety evaluations will be carried out:

· Frequent monitoring of vitals signs during the infusions and for 24 hours after the first infusion

· Clinical assessments (including neurological examination) by the investigators before and after each infusion, and at weekly intervals between drug doses

· Full blood count, coagulation profile, plasma biochemistry (electrolytes, urea, creatinine and liver function tests) and urinalysis before and after each infusion, at 8 hours into the first infusion and at weekly intervals between drug doses

· Cardiac investigations: There was no evidence of cardiac toxicity in the animal studies; however, since CYT997 is a vascular targeting agent, close monitoring for cardiac dysfunction will be performed in all patients. A 12-lead ECG will be performed before and immediately after each infusion, at 8 hours into the first infusion and at weekly intervals during cycle 1. Patients will be monitored by telemetry during each infusion and for 24 hours after the first infusion. A gated blood pool scan to assess left ventricular ejection fraction will be performed at baseline and repeated after every second infusion.

· A chest X-ray and pulmonary function tests (including diffusing capacity) will be performed at baseline and repeated after every second infusion