| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic breast cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b Study
To determine the safety, tolerability, and maximum tolerated dose (MTD) of AV-951 when administered in combination with paclitaxel
Phase 2a Study
To determine the overall response rate of AV-951 in combination with paclitaxel in subjects with previously untreated metastatic breast cancer |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b Study
• To characterize the pharmacokinetic (PK) profile of AV-951 and paclitaxel when administered in combination
• To evaluate the antineoplastic activity of AV-951 and paclitaxel when administered
in combination
• To perform an exploratory study in a subset of patients to evaluate:
o Changes in flow-mediated vasodilation (FMD) during treatment with AV-951
o The relationship between hypertension during AV-951 therapy, FMD and plasma nitrotyrosine (NT) levels
Phase 2a Study
• To determine the duration of complete and partial responses and time to disease progression (TTP)
• To determine safety and tolerability of AV-951 when administered in combination with paclitaxel
• To evaluate the effect of AV-951 and paclitaxel on global and targeted gene expression patterns
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in the study:
1. ≥ 18-year-old females
2. Histologically or cytologically documented invasive breast cancer
3. Documented progressive disease (Phase 1b study) OR documented metastatic disease (Phase 2a study)
4. Prior Treatment:
• Phase 1b study: No more than 4 prior chemotherapy treatments, only 1 prior taxane-based regimen for metastatic disease. There is no limit to the number of prior hormonal or biological treatments.
• Phaes 2a study: No prior chemotherapy or biological therapy for metastatic breast cancer. There is no limit to the number of prior hormonal treatments.
• Prior adjuvant chemotherapy or biological therapy will not be counted in the number of prior treatments, unless recurrence occurs within 12 months of last dose of adjuvant therapy, in which case it will be counted as 1 prior therapy; adjuvant treatment with a taxane is allowed.
5. Measurable or evaluable disease by RECIST criteria (Phase 1b study) (see Appendix A). Subjects to be enrolled in the Phase 2a study are required to have measureable disease according to RECIST.
6. No prior VEGF-TKI drugs such as sunitinib, sorafenib, AZ2171, AG013736, GW786034, ZD6474 AMG706, PTK/ZK and other similar agents.
7. No treatment with bevacizumab within 4 weeks prior to start of protocol therapy, no prior treatment with other VEGF binding antibodies or VEGF-trap.
8. No treatment with the following agents within 3 weeks prior to start of protocol therapy:
• Chemotherapy (at least 6 weeks for nitrosoureas, mitomycin C, and liposomal
doxorubicin)
• Other signal transduction inhibitors and monoclonal antibodies
• Immunotherapy or biological response modifiers
• Any experimental therapy
9. No treatment with radiotherapy within 2 weeks (if involving < 25% of bone marrow), or 4 weeks (if involving ≥ 25% of bone marrow) prior to start of protocol therapy.
10. Resolution of all toxicities associated with prior treatment to ≤ Grade 1 (except for Grade 2 alopecia) prior to start of protocol therapy.
11. ECOG performance status ≤ 2 and life expectancy ≥ 3 months
12. Signed and dated written informed consent |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria are ineligible for participation in the study:
1. Known hypersensitivity to paclitaxel or to any other component of the paclitaxel
formulation.
2. Pregnant or lactating women; all fertile subjects must use effective contraception (barrier method) while on study and for 3 months thereafter. All subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes (a) IUD plus 1 barrier method, or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm.) Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study.
3. Subjects with symptomatic CNS metastases. Subjects with treated brain metastases that have remained stable for at least 3 months without steroids are allowed. Subjects with signs or symptoms or history of brain metastasis must have a CT or MRI scan of the brain within 1 month prior to the start of protocol therapy. Subjects with spinal cord or nerve root compression who have completed treatment at least 4 weeks before the start of protocol therapy and are stable without steroid treatment for at least one week before start of protocol therapy are allowed. Subjects with leptomeningeal metastases are not allowed.
4. Any of the following hematologic abnormalities:
• Hemoglobin < 9.0 g/dL
• ANC < 1500 per mm3
• Platelet count < 100,000 per mm3
5. Any of the following serum chemistry abnormalities:
• Total bilirubin > 1.5 × ULN (>2.5 mg/dL in patients with Gilbert’s syndrome)
• AST or ALT > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)
• GGT > 2.5 x ULN (or > 5 × ULN for subjects with liver metastasis)
• Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone
metastasis)
• Serum albumin < 3.0 g/dL
• Serum creatinine > 1.5 × ULN
• Proteinuria > 2.5 g/24 hours or 3+ with urine dipstick
• Any other ≥ Grade 3 laboratory abnormality at baseline (other than those listed
above)
6. Significant cardiovascular disease, including:
• Clinically symptomatic heart failure.
• Uncontrolled hypertension
7. Baseline neuropathy > Grade 1
8. Subjects with delayed healing of wounds, ulcers, and/or bone fractures
9. Serious/active infection or infection requiring parenteral antibiotics
10. Inadequate recovery from any prior surgical procedure; major surgical procedure within 6 weeks prior to start of protocol therapy.
11. Inability to comply with protocol requirements
12. Ongoing hemoptysis or history of clinically significant bleeding within 6 months to start of protocol therapy.
13. Cerebrovascular accident within 12 months to start of protocol therapy, or peripheral vascular disease with claudication on walking less than 1 block.
14. Deep venous thrombosis or pulmonary embolus within 6 months prior to start of protocol therapy.
15. Subjects with a “currently active” second primary malignancy other than non-melanoma skin cancers. Subjects are not considered to have a “currently active” malignancy if they have completed anti-cancer therapy and have been disease free for > 2 years.
16. Known concomitant genetic or acquired immune suppression disease such as HIV.
17. Treatment with systemic hormonal therapy within 3 weeks prior to start of or during protocol therapy, with the exception of:
• Hormonal therapy for appetite stimulation or contraception
• Nasal, ophthalmic, inhaled and topical steroid preparations
• Oral replacement therapy for adrenal insufficiency
• Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for other conditions
• Hormone replacement therapy
18. Herbal preparations/supplements (except for a daily multivitamin/mineral supplement not containing herbal components) or CYP3A4 inhibitors (see Appendix D) within 2 weeks prior to start of or during protocol therapy.
19. Full dose oral anticoagulation with warfarin, acenocoumarol, fenprocoumon, or similar agents. If previously receiving these type of agents, a minimum washout of 1 week and documented INR < 1.5 x ULN will be required prior to start of protocol therapy. Full dose anti-coagulation with low molecular weight heparin or unfractionated heparin administered subcutaneously is allowed.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine the safety, tolerability, maximum tolerated dose (MTD), and overall response rate of AV-951 when administered in combination with paclitaxel |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Upon completion of 8 wks (2 cycles of AV-951), subjects w/documented stable disease or an objective response may continue to receive AV-951 and paclitaxel therapy at the same dose and schedule previously utilized for up to 1 yr from the subject’s first dose of AV-951 as long as tolerability is acceptable. After 1 yr, treatment may continue if subjects have clinical benefit and tolerability is acceptable; or subjects may return to their standard of care as determined by their investigator. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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