| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The Safety run-in dose escalation part will be performed in subjects with refractory hematological malignancies and do not have effective standard therapies available.
The Phase II part will be performed in older subjects with Poor Prognosis Acute Myeloid Leukemia. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
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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 |
Safety Run-in
To determine the MTD for each of the two regimens of AS703026 in subjects with advanced hematological malignancies
Phase II
To assess the anti-leukemic activity of two regimens of AS703026 in older subjects with newly diagnosed poor prognosis AML, who are not candidates for intensive chemotherapy
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| E.2.2 | Secondary objectives of the trial |
Safety Run-in
To provide preliminary findings on the safety profile of AS703026 in subjects with hematological malignancies.
To assess the PK of AS703026 in subjects with hematological malignancies.
To assess anti-leukemic activity of AS703026 in subjects with hematological malignancies.
Phase II
To determine the safety and tolerability of AS703026 in older subjects with newly diagnosed poor prognosis AML.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Safety Run-in Part
the subjects must fulfill all of the following criteria:
1. Female and male subjects with one of the following conditions:
a. Primary or secondary AML pathologically confirmed according to WHO classification, who meet at least one of the following conditions:
i. Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available,
ii. Subjects refractory to available therapies, for example, who failed to achieve CR after 2 induction chemotherapy treatments,
iii. Newly-diagnosed older subjects (≥75 years of age), not candidates for intensive chemotherapy,
b. Subjects with MDS, IPSS Int-2 or high risk who are resistant or intolerant to standard treatment and are not candidates for transplantation,
c. Subjects with relapsed or refractory MM, who have failed or are intolerant to at least two prior therapies including thalidomide, lenalidomide and bortezomib,
d. Subjects with advanced MPD for whom no established treatment options are available,
e. Subjects with ALL, relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available,
2. Age ≥18 years,
3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments,
4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Males with female partners of childbearing potential and female subjects of childbearing potential must therefore be willing to use adequate contraception as approved by the Investigator, such as oral contraceptives, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. For the purposes of this trial, childbearing potential is defined as “All female subjects after puberty unless they are post-menopausal for at least two years, surgically sterile or sexually inactive”.
Phase II Part
the subjects must fulfill all of the following criteria:
1. Female and male subjects with newly diagnosed primary or secondary AML pathologically confirmed according to WHO classification, who have NOT been exposed to any prior therapy for AML with the exception of (a) emergency leukapheresis and (b) emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before the start of the trial treatment. Note: Prior therapy for preexisting hematological condition e.g. MDS or MPD, including but not limited to hypomethylating agents is allowed until at least 2 weeks or 5 half lives of that agent before the first dose of AS703026.
2. Subjects who meet at least one of the following conditions:
a. Age ≥75 years
OR
b. Age ≥60 and < 75 years with at least one of the following poor prognostic factors:
i. Secondary AML, as determined by known and documented exposure to leukemogenic therapy or environmental toxin,
ii. antecedent history of MDS or myeloproliferative disorder according to WHO criteria for at least 3 months prior to trial entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting the diagnosis,
iii. At least one of the following unfavorable cytogenetic abnormalities: del(5q), –5, –7, del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (≥ 3 unrelated abnormalities),
iv. ECOG Performance status 2.
3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments.
4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Males with female partners of childbearing potential must therefore be willing to use adequate contraception as approved by the Investigator, such as oral contraceptives, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. For the purposes of this trial, childbearing potential is defined as “All female subjects after puberty unless they are post-menopausal for at least two years, surgically sterile or sexually inactive”.
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| E.4 | Principal exclusion criteria |
the subjects must NOT meet any of the following criteria:
1. ECOG performance status 3 or greater,
2. Hyperleukocytosis with > 30x109/L leukemic blasts in peripheral blood,
3. Acute promyelocytic leukemia [t(15;17)],
4. Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first AS703026 dose; except the use of hydroxyurea as permitted in inclusion criteria,
5. Participation in other clinical trials within at least 2 weeks of the first AS703026 dose,
6. Clinical evidence of active CNS leukemia,
7. Active and uncontrolled infection including but not limited to known infection with HIV, active hepatitis B, or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry,
8. Major surgery within two weeks prior to trial entry,
9. Liver function tests above the following limits at the screening: total bilirubin > 1.5 x ULN unless related to Gilbert’s syndrome or hemolysis, AST and/or ALT > 2.5 X ULN, or for subjects with liver involvement AST and/or ALT > 5 x ULN ,
10. INR > 1.5 ULN unless on treatment with warfarin,
11. For female subjects: pregnant or breast-feeding,
12. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product,
13. Has significant cardiac conduction abnormalities and/ or pacemaker,
14. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion,
15. Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study,
16. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such,
17. Other significant disease that in the Investigator’s opinion would exclude the subject from the trial,
18. Legal incapacity or limited legal capacity.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Run-in Part
· Dose-Limiting Toxicity (DLT) using the NCI-CTCAE v3.0, evaluated over the first cycle – Days 1 to 28 for each of the 2 regimens separately.
The number and the incidence of DLTs will be used in the primary statistical analysis of the Safety run-in part
Phase II Part
·Presence of at least one clinical complete remission (CCR) during the treatment period defined as either morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) according to IWG response criteria, as assessed at the end of the first and each subsequent cycle during the treatment period.
The number of subjects with CCR will be used in the primary statistical analysis of the Phase II part
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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
| 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 | 4 |
| 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 |
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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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The trial will continue until all of the following conditions are met:
· All subject stop receiving any Investigational Medicinal Product,
· Post-treatment follow-up period, defined in the protocol as being part of the trial, has been completed for all of the subjects,
· None of the trial-related visits (i.e. requested by protocol) are planned at the site,
· None of the procedures or interventions according to the protocol are being undertaken in any subject.
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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