lyn- trial

[lindaw]

Lyn can you give me more details aboutm the trial. IMy onc is interestedThanks
Lindaw

[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

[Lyn]

Part 2, I don't know the significence of all the "X" symbols maybe onc talk. Did I mention my onc told me to go easy on him, have know idea what he means, tongue in cheek! But I will be asking a lot of questions.

Love & Hugs Lyn

Efficacy Assessments

1. Objective responses. Tumour lesions will be assessed clinically or radiologically (CT or MRI scans), and measurable lesions will be quantified using the RECIST criteria. Evaluation for responses will be made by repeating clinical measurements after each cycle of CYT997 and repeating scans after every second cycle.

2. Vascular-targeting activity. The effects of CYT997 on tumour vasculature will be evaluated using the techniques listed below:

(i) Dynamic contrast-enhanced MRI (DCE-MRI) scans of tumour lesions will be performed before and after the first infusion of CYT997.

(ii) Measurement of viable and apoptotic circulating endothelial cells by flow cytometry will be performed at 0, 8 and 24 hours from starting the first CYT997 infusion.

(iii) Assay of the serotonin metabolite 5-HIAA in blood will be performed before and after the first CYT997 infusion.

(iv) Re-biopsy of tumour lesions one week after the first CYT997 infusion will be performed in patients with accessible tumours (eg., cutaneous or nodal metastases) who give specific informed consent. Samples will be assessed histologically for apoptosis, necrosis and changes in tumour microvasculature.









8. STUDY CALENDAR



Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans and x-rays must be done within 4 weeks prior to the start of therapy.





Pre-
study

Wk 12

Wk
2

Wk
3

Wk
4

Wk
5

Wk
6

Wk
7

Wk
8

Wk
9

Cycles
4-6

Off
study

Pre-inf

8 hr

24 hr

48 hr

72 hr

96 hr

CYT9971





X



X





X





X



Informed consent

X




Demographics/Medical history

X





Concurrent medications

X

X


X

X

X





X





X



Physical exam

X

X



X

X





X

X

X





X





X

X

Vital signs

X

X-----------------------X





X

X

X





X





X

X

Weight

X

X

X

X

X





X





X

X

Urinalysis3

X

X-----------------------X





X

X

X





X





X

X

Performance status

X

X




X





X





X

X

Full blood count

X

X

X

X

X





X

X

X

X

X

X

X

X

X

X

Coagulation profile4

X

X

X

X

X





X

X

X

X

X

X

X

X

X

X

Plasma biochemistry5

X

X

X

X

X





X

X

X

X

X

X

X

X

X

X

Serum pregnancy test6

X




Pharmacokinetic samples7



X-----------------------------------------X


Samples for biological endpoints8



X-----------------------X



X

X




DCE-MRI9



X



X




X




Adverse event evaluation



X--------------------------------------------------------------------------------------------------------------------------------X

X

Tumour measurements

X

Tumour measurements are repeated after every 2nd cycle of CYT997

X10

Radiological evaluation

X

Radiological measurements are performed after every 2nd cycle of CYT997

X10

ECG

X

X

X

X

X





X

X

X





X





X



Gated heart pool scan

X


X



X11



Pulmonary function tests12

X


X




X11



1. Dose as assigned; 24-hour continuous IV infusion

2. Assessments to be performed prior to commencing the CYT997 infusion and at 8, 24, 48, 72 and 96 hours after the start of the infusion

3. Dipstick test; urine microscopy/culture and 24-hour urine protein if abnormal (greater than 1+ of blood or protein)

4. PT, APTT and fibrinogen

5. Electrolytes, bicarbonate, glucose, urea, creatinine, urate, albumin, total bilirubin, alkaline phosphatase, AST, ALT, LDH, calcium and phosphate

6. Women of childbearing potential

7. Blood and urine samples (see Section 7.3)

8. See Section 7.1

9. Dynamic contrast-enhanced MRI scan (see Section 7.2)

10. Two consecutive measurements taken 4 weeks apart must be used to document progressive disease if the patient is removed from study for this reason.

11. Prior to every 2nd cycle of CYT997

12. Spirometry, lung volumes and diffusing capacity

[Lyn]

Hi again. I got this bit of info off the Net?

Love & Hugs Lyn




Australian clinical trial of potent new anticancer drug (CYT997)

Pharmaceutical NewsPublished: Wednesday, 27-Apr-2005http://www.news-medical.net/aspvirtualnews/template_images/print_article.gif Printer Friendly (http://www.news-medical.net/print_article.asp?id=9603) http://www.news-medical.net/aspvirtualnews/template_images/email_article.gif Email to a Friend (http://www.news-medical.net/email_article.asp?id=9603)

Up to 30 patients with advanced incurable solid-tumours are to be involved in clinical trials of a potent new anticancer drug (CYT997), developed by Australian biotechnology company, Cytopia Limited (http://www.cytopia.com.au/).

Cytopia Managing Director, Dr Kevin Healey, said the company had obtained the necessary ethics approvals to begin clinical trials at the Royal Brisbane and Women's Hospital in association with the Queensland Institute of Medical Research and Q-Pharm Pty Ltd. The tests will be supervised by leading ovarian oncologist, Dr Paul Vasey, and medical oncologist, Dr Jason Lickliter.

"In animal studies, CYT997 was highly effective in killing cancer cells including prostate, colon and breast cancer, lymphoma and leukaemia. Based on this success, we are confident to proceed to human clinical trials," Dr Healey said.

"We have completed a rigorous preclinical evaluation of the safety and toxicology of the drug in several animal species that cleared the way for human trials.

"We are very excited about a number of features of the drug. It has a dual mode of action, directly killing cancer cells and at the same time starving the cancer of its blood supply. "Cancers rely on this blood supply for their growth," he said.

Dr Healey said the drug looked like it would be effective when taken orally which would be a major benefit for patients. "In addition, CYT997 appears to avoid some of the mechanisms that enable tumours to become resistant to existing first line drugs," he said.

Cytopia's Chief Scientific Officer, Dr Andrew Wilks said that the Phase I study would be a non-blinded, dose escalation study in patients with various cancers and could take between nine and twelve months. "Patients will receive CYT997 by intravenous infusion once every three weeks for up to six cycles," Dr Wilks said.

The primary goals of this study are to evaluate the safety and tolerability of CYT997, to assess its behavior in vivo and to establish a safe dose of CYT997 for subsequent Phase II clinical trials.

"In addition, we will be looking for signs that the drug is having an effect on the cancers, particularly at the higher doses," he said.

According to the American Cancer Society, there will be about 1.3 million new cases of cancer in the US in 2005, not including skin cancers. Approximately 570,000 deaths are expected in 2005 in the US alone. The National Institutes of Health estimate direct medical costs for cancer in 2004 at $69.4 billion.

Cancer is still the leading cause of death in Australia with more than 36,000 people dying each year. More than 88,000 new cases of cancer are also diagnosed in Australia each year, while one in three men and one in four women will be directly affected by cancer before the age of 75.

http://www.cytopia.com.au/ (http://www.cytopia.com.au/)






http://www.news-medical.net/images/spacer.gif