Symptoms and General Pathology

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All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Nilotinib

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Imatinib-resistant / intolerant PH+ CML-CP patients

Imatinib-resistant / intolerant PH+ CML-AP patients

Novartis Pharmaceuticlas

The purpose of this trial is to assess the efficacy, safety, tolerability, biologic activity, and pharmacokinetics of AMN107 in six groups of patients with one of the following conditions:

Relapsed/refractory Ph+ Acute lymphoblastic leukemia (ALL) (arm 1)

Group A - Imatinib failure only (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)
* imatinib-resistant or intolerant CML - Accelerated Phase (AP)
* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Group B - Imatinib and other TKI failure (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)
* imatinib-resistant or intolerant CML - Accelerated Phase (AP)
* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL) (arm 5)

Systemic mastocytosis (Sm) (arm 6)

A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies

A Phase IA/II Multicenter, Dose-escalation Study of Oral AMN107 on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant/Intolerant CML in Chronic or Accelerated Phase or Blast Crisis, Relapsed/Refractory Ph+ ALL, and Other Hematologic Malignancies.

Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in bone marrow) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in bone marrow).

Hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).

Hematological response was a primary outcome measure for Arm CML-AP with prior imatinib only.

Cytogenetic responses (CyRs) in CML are based on the percentage of Ph+ metaphases in bone marrow; a value of 0% Ph+ metaphases defines a complete cytogenetic response (CCyR) and \>0% to 35% defines a major cytogenetic response (MCyR). Achievement of CCyR is associated with a significant survival advantage in participants with CML-CP. MCyR was categorized as either CCyR or partial cytogenetic response (PCyR).

A Complete Hematologic Response (CHR) is obtained when all the following criteria are met: WBC ≤ institutional ULN; platelets ≤ 450,000/mm3; ≤20% basophils in peripheral blood; no blasts or promyelocytes in PB cells; \< 5% myelocytes plus metamyelocytes in PB cells; no extra-medullary involvement including no hepatomegaly or splenomegaly.

MMR was defined for participants who demonstrated a reduction in BCR-ABL/control gene % transcripts to ≤0.1% based on international scale. The control gene used may have been either BCR or ABL.

Time to Progression was defined as the time from the start of nilotinib to the earliest date of Disease Progression (PD), discontinuation due to PD or death.

Disease progression was defined as an increase in the number of circulating leukemic cells via cytogenetic assessment using real-time quantitative reverse transcriptase polymerase chain reaction (PCR).

OS was calculated for all participants as the time between the start of nilotinib and death. Participants were followed for survival after discontinuation, every 3 months, and were included in the analysis of OS. Censoring was at the date of the last contact for discontinued participants and followed up for survival.

Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.

Novartis Pharmaceuticals

Safety set: All participants who received at least one dose of study medication and had at least one post baseline safety assessment.

Adult participants PH+ CML-CP without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

CML-CP With Prior Imatinib Only

Adult participants Ph+ CML-AP without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

CML-AP With Prior Imatinib Only

Adult participants Ph+ CML-CP in addition to prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

CML-CP

Adult participants PH+ CML-AP without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

Adult participants PH+ CML-CP in addition to prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

Total

<35 years

≥35 to <55 years

≥55 to <65 years

≥65 years

Age, Customized

Sex: Female, Male

Study Director

Adult participants PH+ CML-AP (Accelerated Phase Chronic Myeloid Leukemia) without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

Full Analysis Set (FAS): All participants who received at least one dose of study medication

Number of Participants With Major Cytogenetic Response (MCyR)

Full Analysis Set (FAS): All participants who received at least one dose of study medication.

Number of Participants Confirmed Overall Hematological Response (Phase II)

Number of Participants With Overall Major Cytogenetic Responses (Phase II)

Number of Participants With Complete Hematologic Response (Phase II)

Full Analysis Set (FAS): All participants who received at least one dose of study medication.

Major molecular response was not an efficacy variable for participants who received the CML-CP with prior imatinib and other TKI (Group B E8)

Participants With (MMR) Major Molecular Response (Phase II)

Full Analysis Set (FAS): All participants who received at least one dose of study medication.

Time to progression was not an efficacy variable for participants who received the CML-CP with prior imatinib and other TKI (Group B E8).

Time to Progression (TTP) (Phase II)

Overall Survival (OS) (Phase II)

Serious Adverse Events

Adverse Events

Adult participants PH+ CML-CP ( Chronic Phase Chronic Myeloid Leukemia) without prior TKI treatment with either resistant / intolerant to Imatinib received 400 mg Nilotinib orally twice daily up to the end of treatment (September-2012).

Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety

Overall Study

This study will investigate if nilotinib provides an improved safety and efficacy profile over that seen in patients receiving Imatinib.

A Phase l/ll Study of AMN107 in Adult Patients With Glivec-intolerant CML or Relapsed-refractory Ph+ALL

A Phase I/II Multicenter, Dose-escalation Study of Oral Nilotinib on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant or Imatinib-intolerant CML, or Relapse/Refractory Ph+ALL

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Blinatumomab

Ponatinib

patients will receive induction with ponatinib followed by at least 2 cycles of blinatumomab

patients will receive a combination of imatinib and chemotherapy.

Patients aged 18-65 will receive Ponatinib at the dose of 45 mg/day for the first 22 days and then will reduce the dose to 30 mg (depending on the morphologic and molecular response), whereas patients older than 65 years will start Ponatinib at 30 mg/day, in order to avoid TAEs. Patients will continue treatment with Ponatinib up to day 70 (10 weeks of treatment), except for disease progression, intolerable toxicity, or withdrawal from study. Thereafter:

* Patients will receive Blinatumomab (minimum 2 cycles, up to a maximum of 5).
* Patients not achieving a CHR after 2 cycles of Blinatumomab will go off-study. After the 2 cycles of Blinatumomab patients aged 18-65 will be stratified for transplant allocation

Ponatinib + Blinatumomab

patients aged 18-65 will receive chemotherapeutic scheme combined with Imatinib. Elderly patients will receive Imatinib plus mild chemotherapy.

Chemotherapy + Imatinib

Paola Fazi

Enrico Crea

Piero Galieno

Crescenza Pasciolla

Alessandro Rambaldi

Federico Mosna

Erika Borlenghi

Renato U Bassan

Mario Luppi

Catello Califano

Maria Paola Martelli

Giuseppe Visani

Daniele C Vallisa

Sabina Chiaretti

Nicola Cascavilla

Monica Bocchia

Anna Candoni

This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients based on the combination of Ponatinib with Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (\>65 years old).

Patients will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

This is a randomised, open-label, multicenter, phase III study for adult de novo Ph+ ALL patients (≥18 years, no upper age-limit) based on the combination of the pan-TKI Ponatinib, with the bispecific monoclonal antibody Blinatumomab. The control arm will be represented by a chemotherapeutic scheme combined with Imatinib for patients aged 18-65 and by Imatinib plus age-adjusted chemotherapy for elderly patients (\>65 years old).

Patients (≥18 years, no upper age limit) will be randomized 2:1 to receive the experimental or control arm. If patients in the control arm do not achieve a CHR and/or MRD negativity, after the sixth consolidation cycle (week 20), a crossover to receive Blinatumomab is planned. Likewise, if patients in the control arm develop an ABL1 mutation at any time of treatment, they will switch to experimental arm. HLA typing will be performed immediately after diagnosis in both arms for patients aged up to 65 years.

After the 2 cycles of Blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18-65 will be stratified for transplant allocation.

Sequential Treatment With Ponatinib and Blinatumomab vs Chemotherapy and Imatinib in Newly Diagnosed Adult Ph+ ALL

Newly Diagnosed Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL). Sequential Treatment With Ponatinib and the Bispecific Monoclonal Antibody Blinatumomab vs Chemotherapy and Imatinib

Gruppo Italiano Malattie EMatologiche dell'Adulto

Study to Evaluate Nilotinib in Adult Patients With Imatinib-resistant or Imatinib-intolerant Chronic Myelogenous Leukemia (CML), or Relapse/Refractory Ph+ Acute Lymphoblastic Leukemia (ALL) (Extension Study)

A Phase I/II Multicenter, Dose-escalation Study of Oral Nilotinib on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant or Imatinib-intolerant Chronic Myelogenous Leukemia (CML), or Relapse/Refractory Ph+ALL (Philadelphia Positive Acute Lymphocytic Leukemia)(Extension Study)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies	NCT00109707	Chronic Myeloge... Acute Lymphobla... Hypereosinophil... Systemic Mastoc...	Nilotinib	18 Years -	Novartis
A Phase l/ll Study of AMN107 in Adult Patients With Glivec-intolerant CML or Relapsed-refractory Ph+ALL	NCT00384228	Chronic Myeloge... Acute Lymphobla...	Nilotinib	20 Years -	Novartis
Sequential Treatment With Ponatinib and Blinatumomab vs Chemotherapy and Imatinib in Newly Diagnosed Adult Ph+ ALL	NCT04722848	Acute Lymphobla... ALL, Adult Philadelphia-Po...	Ponatinib + Bli... Chemotherapy + ...	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Study to Evaluate Nilotinib in Adult Patients With Imatinib-resistant or Imatinib-intolerant Chronic Myelogenous Leukemia (CML), or Relapse/Refractory Ph+ Acute Lymphoblastic Leukemia (ALL) (Extension Study)	NCT01279473	Chronic Myeloge... Acute Lymphobla...	Nilotinib	20 Years -	Novartis

Spots Global Cancer Trial Database for acute lymphoblastic leukemia (philadelphia chromosome positive)