E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients who have benefited from cytotoxic chemotherapy. Patients will have either metastatic soft-tissue or bone sarcoma, with histological category (soft-tissue or bone) as one of the baseline stratification factors. Importantly, in this trial, bone sarcoma patients must have visceral metastatic disease (e.g., metastatic to lung or liver), or have achieved response of visceral metastasis. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10041299 |
E.1.2 | Term | Soft tissue sarcomas |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006008 |
E.1.2 | Term | Bone sarcoma NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare progression-free survival (PFS) of patients who have achieved complete response, partial response or stable disease following first, second or third line chemotherapy when treated with AP23573 versus placebo. |
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E.2.2 | Secondary objectives of the trial |
1. To compare the overall survival (OS) of patients when treated with AP23573 versus placebo.
2. To compare the best target lesion response of patients receiving AP23573 versus placebo.
3. To assess changes in cancer-related symptoms in those patients treated with AP23573 compared to those treated with placebo.
4. To determine the safety and tolerability of AP23573. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A Pivotal Trial to Determine the Efficacy and Safety of AP23573 when Administered as Maintenance Therapy to Patients with Metastatic Soft-Tissue or Bone Sarcomas
Protocol number: AP23573-07-302
Amendment 4: V1.4 10 November 2008
A sub-study of the above mentioned protocol is intended to study potential biomarkers (in consenting patients) that are related to clinical outcome or to patient response to AP23573. Details relating to this biomarker study are provided in section 13.5.3 of the above mentioned protocol. |
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E.3 | Principal inclusion criteria |
1. Documented histologic diagnosis of soft-tissue or bone sarcoma that has metastasized, with the exception of certain histopathologic subtypes of sarcomas recognized by experts to derive no benefit from conventional chemotherapies or with distinctly different natural histories. See Attachment G for a list of excluded sarcoma sub-types.
2. Ongoing complete response, partial response or stable disease as defined by RECIST guidelines after a minimum of 4 cycles (and maximum of 12 months) of any one of 1st, 2nd or 3rd line of prior cytotoxic chemotherapy for metastatic disease.
3. Disease status (SD or better response) confirmed by a central review of at least the 2 most recent radiological evaluations (e.g., CT or MRI scans) obtained a minimum of 6 (± 1 week) and a maximum of 12 weeks (± 1 week) apart.
4. Patients with partial response or stable disease at study entry must have least one measurable or evaluable lesion as defined by RECIST guidelines (see protocol Attachment D)
5. Patients with only bone metastases are excluded.
6. ECOG performance status of 0 or 1 (see protocol Attachment A)
7. Male or female patients ≥ 13 years of age (patients 13-17 years of age must weigh at least 100lbs. (45.4 kg)). In regions where applicable local law prohibits enrollment of patients <18 years of age, only patients ≥18 years of age will be eligible.
8. Patients must have normal organ and marrow function as defined below:
• leukocytes ≥ 3,000/μL
• absolute neutrophil count ≥ 1,500/μL
• platelets ≥ 100,000/μL
• total bilirubin below institutional upper limit of normal (unless patient has Gilbert’s disease in which case ≤1.5 x ULN)
• AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal (or ≤ 5 x ULN if liver metastases are present)
• creatinine ≤1.5 X ULN for the institution (or calculated creatinine clearance ≥ 50 mL/min/1.73 m2)
9. Serum cholesterol ≤ 350 mg/dL and triglycerides ≤ 400 mg/dL
10. Male and female patients who are not surgically sterile or postmenopausal must agree to use reliable methods of birth control from time of screening until 30 days after the last dose of the study drug
11. Able to understand and willing to sign a written informed consent document
12. Completed 1st, 2nd or 3rd line chemotherapy and having received the last dose ≥ 3 and ≤ 12 weeks (± 1 week) prior to randomization
13. Randomization and treatment to begin ≤ 12 weeks (± 1 week) following previous chemotherapy
14. No brain or CNS metastasis, unless successfully treated (i.e., controlled for > 3 months |
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E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating
2. Presence of known or active brain or CNS metastases, unless successfully treated (i.e., controlled for> 3 months)
3. Prior therapy with rapamycin or rapamycin analogs, including AP23573
4. Ongoing toxicity associated with prior anticancer therapy ≥ Grade 2 (excluding alopecia) according NCI common terminology criteria
5. Another primary malignancy within the past three years (except for non-melanoma skin cancer and cervical carcinoma in situ)
6. Known Grade 3 or 4 hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin)
7. Concomitant treatment with medications that induce or inhibit CYP3A. Patients should be off these medications ≥ 2 weeks prior to the first dose of AP23573
8. Significant uncontrolled cardiovascular disease
9. Active infection requiring systemic therapy
10. Known HIV infection
11. Concurrent treatment with immunosuppressive agents other than prescribed corticosteroids at stable doses for ≥ 2 weeks prior to first planned dose of study drug
12. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 2 weeks prior to the first dose of study drug (with the exception of minor procedures, e.g., central venous access port placement)
13. Presence of any life-threatening illness or organ system dysfunction which, in the option of the Investigator, would either compromise the patient’s safety or interfere with evaluating the safety of the study drug |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival, defined as the time from the date of randomization to the date of documented progressive disease, recurrence or death (whichever occurs first) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 8 weeks until progressive disease is documented or another anti-cancer therapy is instituted, whichever occurs first.
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E.5.2 | Secondary end point(s) |
(1) Overall survival defined as the time from the date of randomization to the date of death; (2) best target lesion response, defined as best change in sum of the target lesions
from baseline to disease progression; (3) changes in select cancer-related symptoms; and (4) safety and tolerability.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) Overall survival will be assessed at 3-month intervals after discontinuation; (2) best target lesion response will be assessed every 8 weeks until progressive disease is documented or another anti-cancer therapy is instituted, whichever occurs first; (3) cancer-related symptoms will be assessed every 4 weeks while on treatment; and (4) safety and tolerability will be assessed at each visit. |
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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 | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 | No |
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 |
Australia |
Brazil |
Canada |
Chile |
Czech Republic |
France |
Germany |
Greece |
India |
Israel |
Italy |
Korea, Democratic People's Republic of |
Mexico |
New Zealand |
Peru |
Poland |
Slovakia |
South Africa |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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Six months after all patients have completed all study visits or have otherwise completed the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |