Novartis Panobinostat Refractory AML

A Phase II Study of Oral Single Agent Panobinostat in Patients with Refractory de novo or secondary Acute Myelogenous Leukemia (AML)

Stratum A specific inclusion criterion:
Refractory AML with confirmed initial diagnosis of de novo AML (excluding APL)

Stratum B specific inclusion criterion:
Refractory AML with confirmed initial diagnosis of AML (excluding APL) secondary to precedent AHD or MDS with either condition being diagnosed at least three months before confirmed diagnosis of AML [Patients may have e received no prior treatment or treatment with conventional care regimens [including best supportive care , low dose cytarabine, intensive chemotherapy, hypomethylating agents (azacitidine, decitabine), or other therapies
(e.g. lenalidomide)] for precedent MDS.

Stratum A or B general inclusion criteria:
1. Written informed consent prior to study-specific screening procedures
2. Age ≥18 years old
3. Patients with refractory AML (according to Estey 1996b)], whose disease:
• is primary refractory (= no complete remission following initial induction therapy),
OR
• has relapsed within 12 months after CR1 and for whom salvage (re-induction) chemotherapy is not indicated for documented clinical reasons OR documented patient refusal OR
• has relapsed within 12 months after CR1 and patient has failed one salvage (reinduction) (Failure or relapse after CR2)
4. Eastern Cooperative Group (ECOG) performance status ≤ 2
5. Laboratory values as follows:
• Electrolyte panel WNL for the institution (potassium and magnesium values < lower limit of normal must be corrected to WNL prior to dosing)
• Total calcium (corrected for albumin) or ionized calcium WNL for the institution
• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN (NCI CTCAE Gr 1)
• Serum creatinine ≤ 1.5 x ULN (NCI CTCAE Gr 1)
• Serum bilirubin ≤ 1.5 x ULN unless attributed to underlying disease (NCI CTCAE Grade 1)
• INR ≤ 1.5 and PTT WNL. Patients receiving anticoagulation therapy (e.g. coumadin, heparin) are eligible provided anticoagulation therapy can be discontinued or changed to parenteral medications while the platelet count is less than 50,000/mm3
• Negative serum pregnancy test (within 7 days of first dose)
• Negative urine pregnancy test immediately prior to first dose
• Clinically euthyroid (hypothyroidism corrected with supplementation is permitted)
6. Patient has received a minimum of one and a maximum of three administrations of conventional remission induction therapy (this may include consolidation and/or HSCT) for newly diagnosed AML.
7. Previous therapy for AML has stopped at least 2 weeks or at least five half lives whichever is longer, before the first dose of study drug
8. Patient has recovered from toxicity of previous AML treatment, including Grade ≤ 1 nonhematologic toxicity prior to the first dose of study drug

Stratum A or B general exclusion criteria

1. Patients with initial diagnosis of AML secondary to ionizing radiation/cytotoxic therapy (e.g. alkylating agents) for previous malignancy
2. Patients requiring valproic acid for any medical condition during the study or within 5 days prior to the first dose of study drug
3. Clinical symptoms suggesting CNS leukemia (patients with neurologic symptoms must undergo lumbar puncture and a CT scan or MRI of the brain to exclude CNS involvement
4. Patients receiving supportive therapy related to complications of allogeneic transplantation, including infections or GVH directed therapy
5. Patients who have received either hydroxyurea or glucocorticosteroids for prevention of leukostasis less than 24 hours before the fist dose of study drug
6. Patients with another malignancy (with the exception of prior MDS in patients with initial diagnosis of AML secondary to MDS/AHD) unless disease-free for at least 3 years following the completion of curative intent therapy. Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasm regardless of the disease-free duration, are eligible if definitive treatment for the condition has been completed.
7. Patients with impaired cardiac function including any of the following:
• Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmias,clinically significant resting bradycardia (<50 beats per minute), QTcF ≥ 450 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
• LVEF< lower limit of institutional normal, as assessed by ECHO or MUGA

• Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria
• Angina pectoris or acute MI within 6 months
• Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen)
8. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause) or history of serious organ dysfunction or disease involving the heart, kidney or liver and/or known seropositive HIV (HIV screening testing is not required)
9. Patient has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled vomiting, grade > 1 diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
10. Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or would impact study participation or follow-up
11. Concurrent use of medications that have a relative risk of prolonging the QT interval or of inducing Torsade de Pointes, if such treatment cannot be discontinued or switched to a different medication prior to the first dose of study drug
12. Female patients who are pregnant or breast-feeding or patients of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been postmenopausal for at least 12 consecutive months (i.e. has had menses any time in the preceding 12 consecutive months).
13. Male patients whose sexual partner(s) are women of childbearing potential (WOCBP) who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.
14. Patient is receiving concurrent immuno, gene, or biologic therapy
15. Patient is unable to swallow capsules

Research Nurse

Alex Stichler

Tel 01132068577

Email alex.stichler@leedsth.nhs.uk

Principal Investigator

Dr Bowen

Tel 01132068481

Email david.bowen@leedsth.nhs.uk

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