A phase I study of the safety, tolerability, and antitumor activity of escalating doses of combretastatin A4 phosphate given in combination with bevacizumab to subjects with advanced solid tumors
| ISRCTN | ISRCTN96787846 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN96787846 |
| ClinicalTrials.gov number | NCT00395434 |
| Secondary identifying numbers | OXC4P1-105 |
- Submission date
- 30/10/2006
- Registration date
- 21/12/2006
- Last edited
- 13/11/2013
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Not provided at time of registration
Contact information
Dr Paul Nathan
Scientific
Scientific
Mount Vernon Hospital
Northwood
Middlesex
HA6 2RN
United Kingdom
| Phone | +44 (0)1923 84 4729 |
|---|---|
| nathan.pd@gmail.com |
Study information
| Study design | Open-label multi-centre ascending-dose single-arm study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Multi-centre |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | |
| Study objectives | 1. To determine the safety and tolerability of three dose levels of Combretastatin A4 Phosphate (CA4P) given IntraVenously (IV) in combination with bevacizumab every 14 days in subjects with advanced solid tumours. The Maximum Tolerated Dose (MTD) will be defined if it is at one of the three dose levels under study 2. To obtain preliminary information on the anti-tumour activity of CA4P when administered in combination with bevacizumab 3. To assess the pharmacodynamic anti-tumour activity of CA4P in combination with bevacizumab utilising Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) for those patients with suitable lesions 4. To obtain pharmacokinetic information on the combination of CA4P and bevacizumab 5. To assess the effect of CA4P alone and the combination of CA4P and bevacizumab on circulating Endothelial Progenitor Cells (EPCs) Please note that the anticipated end recruitment date of this trial has been extended to September 2007. The previous anticipated end date of this trial was 30/06/2007. |
| Ethics approval(s) | NHS Leeds (East) Research Ethics Committee, 27/06/2006, REC reference number: 06/Q1206/89 |
| Health condition(s) or problem(s) studied | Advanced solid tumours |
| Intervention | CA4P will be given IV as a single agent therapy on day one and then once every 14 days in combination with bevacizumab beginning on day eight. Three subjects will be evaluated at each dose level (three dose levels). If a Dose-Limiting Toxicity (DLT) is seen in one subject, the cohort will be expanded to six subjects. If two or more subjects experience a DLT, the cohort at the preceding level will be expanded to six subjects. If the MTD is not found to be at one of the three dose levels under study, no further dose escalation will be performed. At the end of the treatment schedule, if a subject is showing clinical benefit, the subject may continue to receive additional cycles at the discretion of the Principal Investigator (PI) and agreement of the sponsor. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Combretastatin A4 Phosphate (CA4P) and bevacizumab. |
| Primary outcome measure | To determine the safety and tolerability of three dose levels of CA4P given IV in combination with bevacizumab every 14 days in subjects with advanced solid tumors. The MTD will be defined if it is at one of the three dose levels under study. |
| Secondary outcome measures | 1. To obtain preliminary information on the antitumor activity of CA4P when administered in combination with bevacizumab 2. To assess the pharmacodynamic anti-tumor activity of CA4P in combination with bevacizumab utilising DCE-MRI for those patients with suitable lesions 3. To obtain pharmacokinetic information on the combination of CA4P and bevacizumab 4. To assess the effect of CA4P alone and the combination of CA4P and bevacizumab on circulating EPCs |
| Overall study start date | 15/09/2006 |
| Completion date | 01/09/2007 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | ~12 (3-6 per dose group) |
| Key inclusion criteria | 1. Histopathologically or cytologically confirmed malignant solid tumours that have failed standard therapy or for which no life prolonging treatment exists 2. Measurable disease as defined by the Response Evaluation Criteria In Solid Tumours (RECIST) criteria 3. At least four weeks since any prior immunotherapy, chemotherapy or radiation therapy prior to first dose of study drug (six weeks for therapy known to be associated with delayed toxicity such as nitrosoureas or mitomycin-C) 4. Age more than or equal to 18 years old 5. Adequate bone marrow function: a. Absolute granulocyte count (neutrophils and bands) more than 1500 cells/mm^3 b. Platelet count more than 100,000 cells/mm^3 c. Haemoglobin more than 9 g/dL 6. Adequate renal function (Glomerular Filtration calculated by Cockcroft/Gault formula or measure urine creatinine clearance more than 50 mL/minute) 7. Adequate hepatic function: a. Bilirubin less than 1.5 mg/dL b. Aspartate Transaminase (AST) and Alanine Transaminase (ALT) less than 2.5 times the institutional Upper Limit of Normal (ULN) (or less than five times ULN if liver metastases are present) 8. Eastern Cooperative Oncology Group (ECOG) performance status zero to two 9. Life expectancy of more than or equal to 12 weeks 10. Written, signed, dated, and witnessed (if applicable as per International Conference on Harmonisation [ICH] guidelines) Independent Ethics Committee (IEC) approved informed consent form before any study specific screening procedures are performed 11. Fertile subjects must abstain from sexual intercourse or use effective birth control 12. All Women Of Child-Bearing Potential (WOCBP) must have a negative serum pregnancy test within 72 hours of first dose |
| Key exclusion criteria | 1. Contraindications, allergies or sensitivity to the use of the study medications or any other products required for participation in this study (i.e. contrast agents) 2. Presence of Central Nervous System (CNS) metastases 3. Diagnosed Squamous Non-Small Cell Lung Cancer (NSCLC) 4. History of Gastrointestinal Perforations 5. Surgery within 28 days of screening visit or a surgical incision that is not fully healed. Any surgery planned during the study period 6. Proteinuria more than 1 g/24 hours by 24 hour urine collection (perform 24 hour urine collection if more than 1+ on dipstick) 7. Recent haemoptysis (occurrence within the past three months) 8. Prior therapy with CA4P or bevacizumab, or other agents which target Vascular Endothelial Growth Factor (VEGF) or Vascular Endothelial Growth Factor Receptor (VEGFR) signalling such as Sorafenib and Sutent 9. Prior radiation involving more than 30% of the bone marrow 10. Radical radiotherapy to the thorax or abdomen at any time or post-operative radical radiotherapy to the pelvis. Palliative radiotherapy treatments are acceptable. Subjects with rectal primaries who have received pre-operative pelvic radiotherapy or chemoradiation are eligible if the small bowel was mobile and not stuck to the tumour 11. Active autoimmune disorder(s) 12. Immuno-compromised, including subjects known to be Human Immunodeficiency Virus (HIV) positive 13. Active infection requiring antibiotic therapy or any other serious intercurrent illness 14. History of angina (stable or severe, even if controlled with medications), myocardial infarction, Congestive Heart Failure (CHF), non-controlled atrial arrhythmias or clinically significant arrhythmias including conduction abnormality, nodal junctional arrhythmias and dysrhythmias, sinus bradycardia or tachycardia, supraventricular arrhythmias, atrial fibrillation or flutter, syncope or vasovagal episodes 15. Electrocardiogram (ECG) with evidence of prior myocardial infarction (e.g., significant Q waves), QTc more than 450 msec or other clinically significant abnormalities 16. Taking any drug(s) known to prolong the QTc interval, which cannot be interrupted for at least four days during each treatment cycle 17. Known significant heart wall abnormality or heart muscle damage as evidenced on Multiple Gated Acquisition (MUGA) scan or echocardiogram (this is not a required screening investigation) 18. Uncontrolled hypertension (defined as blood pressure consistently greater than 150/100 irrespective of medication), or controlled hypertension requiring use of more than two classes of anti-hypertensives 19. Uncontrolled hypokalemia and/or hypomagnesemia 20. Symptomatic peripheral vascular disease or cerebrovascular disease 21. Psychiatric disorders or other conditions rendering subjects incapable of complying with the requirements of the protocol 22. Receiving concurrent hormonal therapy with exception of gonadotropin-Releasing Hormone (GnRH) agonists in subjects with hormone refractory prostate cancer, Hormone Replcaement Therapy (HRT), oral contraceptive, and megestrol acetate used for anorexia/cachexia 23. Receiving anticoagulation with warfarin, heparin or low molecular weight heparin other than low dose (1 mg) warfarin for maintenance of central line patency 24. Women who are currently pregnant, nursing, or planning a pregnancy; or women who have a positive pregnancy test 25. Receiving concurrent antineoplastic therapy (radiation therapy, cytotoxic or biologic therapy) 26. Participation in an investigational drug or device trial within 30 days of entering the study |
| Date of first enrolment | 15/09/2006 |
| Date of final enrolment | 01/09/2007 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Mount Vernon Hospital
Middlesex
HA6 2RN
United Kingdom
HA6 2RN
United Kingdom
Sponsor information
OXiGENE, Inc. (USA)
Industry
Industry
230 Third Ave
Waltham
MA 02451
United States of America
| Phone | +1 781 547 5900 |
|---|---|
| oxigeneclinical@oxigene.com | |
| Website | http://www.oxigene.com |
"ROR" |
https://ror.org/00cj7p033 |
Funders
Funder type
Industry
OXiGENE, Inc. (USA)
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 15/06/2012 | Yes | No |
