E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myeloid leukemia
Acute lymphoblastic leukemia
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E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia
Acute lymphoblastic leukemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 |
Pase Ib: To evaluate the safety and tolerability of palbociclib in patients with MLL-rearranged leukemia
Phase IIa: To assess the overall response rate to palbociclib, including CR, CRi, PR, and ALE |
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E.2.2 | Secondary objectives of the trial |
- Assessment of RFS and OS
- Evaluation of target (CDK6) inhibition by palbociclib
- Assessment of QoL |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with confirmed diagnosis of acute leukemia with MLL rearrangement according to the 2008 WHO Classification:
- Patients with MLL-rearranged leukemia who are refractory to standard induction therapy and not immediate candidates for allogeneic HSCT (bridge to transplant is allowed)
-Patients with MLL-rearranged leukemia who relapsed after standard first-line treatment and are not immediate candidates for allogeneic HSCT (bridge to transplant is allowed)
-Patients with newly diagnosed MLL-rearranged leukemia who are not eligible for intensive first-line therapy
• Genetic/histologic/immunohistologic assessment in one of the central laboratories
• Age ≥ 18 years, no upper age limit
• WHO performance status of ≤ 2
• No prior chemotherapy two weeks before study entry except hydroxyurea to control hyperleukocytosis
• Non-pregnant and non-nursing. Women of child-bearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 72 hours prior to registration (WOCBP is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 months).
• Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and for three months after the last dose of therapy.
• Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner’s vasectomy). Hormonal contraception is an inadequate method of birth control.
• Men must agree not to father a child and must use a latex condom during any sexual contact with WOCBP while receiving therapy and for three months after therapy is stopped, even if they have undergone successful vasectomy.
• Signed written informed consent
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E.4 | Principal exclusion criteria |
• Prior treatment with palbociclib
• Performance status > 2 according to WHO criteria
• Organ insufficiency: creatinine > 1.5 x upper normal serum level; bilirubin, AST, or AP > 2.5 x upper normal serum level; heart failure NYHA III/IV; uncontrolled hypertension; unstable angina; serious cardiac arrhythmia; severe obstructive or restrictive ventilation disorder
• Uncontrolled infection
• Patients with a “currently active” second malignancy other than non-melanoma skin cancer. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
• Severe neurologic or psychiatric disorder interfering with ability of giving informed consent
• Known or suspected active alcohol or drug abuse
• Known positivity for HIV, active HAV, HBV, or HCV infection
• Bleeding disorder unrelated to leukemia
• Uncontrolled CNS involvement (treatment for CNS-involvement prior to inclusion is allowed)
• QTc > 470 msec (based on the mean value of triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome, or known history of QTc prolongation or Torsade de Pointes
• Uncontrolled electrolyte disorders that can aggravate the effects of a QTc-prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)
• No consent for registration, storage, and processing of individual disease characteristics, information on the course of the disease, and information obtained from the family physician and/or other physicians involved in the treatment of the patient about study participation
• No consent for biobanking
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoint: Type, frequency, severity (graded using the NCI CTCAE Version 4.0), timing, and relatedness of hematologic and non-hematologic toxicities observed during treatment with palbociclib
Primary Efficacy Endpoint: Best response to palbociclib, including CR, CRi, PR, and ALE
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints of the phase Ib study, Safety and Tolerability, will be evaluated continuously during the Phase Ib. The primary endpoint of the phase IIa study, overall response rate, will be evaluated at the end of trial (Feb. 2018) |
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E.5.2 | Secondary end point(s) |
• Relapse-free and overall survival of patients with MLL-rearranged leukemia treated with palbociclib
• Target (CDK6) inhibition by CDK6 activity in circulating blast cells
• Quality of life
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary endpoints will be analyzed at the same time point as the primary endpoints in an exploratory manner |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
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 |
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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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 30 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
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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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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 |