Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia.

NCT01641107 | Completed Phase 2

• 2 other identifiers: LAL18112012-002761-35
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 42

Brief Summary

Drug resistance resulting from emergence of Imatinib-resistant BCR-ABL clones is a significant problem in Ph positive ALL patients because after a very good initial response to one TKI inhibitor, many patients relapse within one year, relapse being almost always associated with a BCR-ABL kinase domain point mutation. The patients who relapse after treatment with one TKI can be rescued to remission with another TKI, but the second remission is usually shorter than the previous one. A more potent TKI inhibitor, and pan-active not only on all the BCR-ABL variants (including the second generation TKI resistant T315I mutant), but also on others molecular targets can do better. In this context, Ponatinib is a novel synthetic orally active tyrosine kinase inhibitor (TKI), specifically developed to inhibit BCR-ABL, the fusion protein that is the product of the Philadelphia chromosome (Ph) in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (Ph+ ALL). It potently inhibits the BCR-ABL protein as well as mutated forms of the protein that arise in patients resistant to prior therapies with TKIs. Ponatinib has been demonstrated to inhibit all the mutations that have been detected so far, in vitro and in vivo and to uniformly suppress the emerge of single-mutant clones in a mutagenesis assay. In the Phase II study, 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients treated with Ponatinib achieved major hematologic response, 47% had a major cytogenetic response, 38% obtained a complete cytogenetic response, showing that Ponatinib provides significant benefit despite previous intolerance or refractoriness to other TKIs. The Phase I trial showed that patients with a more recent diagnosis had increased rates of major molecular response: 79% for 14 patients with 0 to 5 years since diagnosis vs. 29% for 14 patients with more than 5 to 9 years since diagnosis (P=0.02) and 27% for 15 patients with more than 9 to 24 years since diagnosis (P=0.009). These characteristics support the hypothesis for a role of Ponatinib not only in patients resistant to prior TKI therapy but also in untreated ALL Ph+ patients, in order to prevent the emergence of resistant caused by the selection of mutated Ph+ clones and in order to avoid rapid progression of the disease.

Conditions

Philadelphia Positive; BCR-ABL Positive; Acute Lymphoblastic Leukemia

Keywords

Ph+; BCR-ABL+; ALL; Ponatinib; stem cell transplantation

Outcome Measures

Primary Outcomes (1)

• Proportion of patients who are in Complete Hematological Response (CHR).

  The primary endpoint is the proportion of patients who are in CHR at 6 months, calculated on the total number of patients who have been enroled and have received at least one dose of the first drug (prednisone).

  At 6 months from study entry.

Secondary Outcomes (12)

• The rate of Complete Hematological Response (CHR).

  At 6, 12, 24, 36 and 48 weeks from study entry.

• The rate of complete Cytogenetic Response (CgR).

  At 6, 12, 24, 36 and 48 weeks from study entry.

• Duration of Complete Cytogenetic Response (CCgR).

  After four years from study entry.

• The rate of Complete Molecular Response (CMoIR).

  At 12, 24, 36 and 48 weeks from study entry.

• The rate of major molecular response.

  At 12, 24, 36 and 48 weeks from study entry.

Study Arms (1)

Ponatinib

EXPERIMENTAL

Drug: Ponatinib

Interventions

Ponatinib DRUG

Treatment: Patients will receive daily oral administration of Ponatinib at a dose of 45 mg/day for 6 weeks (defined as one course) for 8 courses, same dose and schedule, for a total of 48 weeks. Each patient will be followed for the subsequent 24 months, every 3 month, providing survival information and monitoring serious adverse event. Each patient should be treated for a minimum of 6 weeks. Patients must be discontinued from the trial in the event of myocardial infarction or stroke, or for development or progression of arterial disease necessitating revascularization. Once a complete hematologic response has been achieved, with a platelet count ≥ 50x109/L, patients can be treated with aspirin and/or a statin as clinically indicated, at investigator discretion.

Ponatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To be classified as having Ph+ ALL, patients must have \>20% blasts in bone marrow at the time of diagnosis and no prior history of CML.
• Patients with previously untreated Ph+ and/or BCR/ABL + ALL:
• age ≥ 60 years old or
• age ≥ 18 years old, but unfit for program of intensive therapy and allogeneic SCT
• Adequate hepatic function as defined by the following criteria:
• total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
• alanine aminotransferase (ALT) ≤2.5 × ULN
• aspartate aminotransferase (AST) ≤2.5 × ULN.
• Adequate pancreatic function as defined by the following criterion:
• \- serum lipase and amylase ≤1.5 × ULN.
• For females of childbearing potential, a negative pregnancy test must be documented prior to randomization.
• Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment.
• Signed written informed consent according to ICH/EU/GCP and national local laws.

You may not qualify if:

• WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
• Active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubin ≥ 1.5 x ULN.
• History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
• History of alcohol abuse.
• Ongoing or active infections.
• Uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL).
• Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
• any history of myocardial infarction, stroke, or revascularization
• unstable angina or transient ischemic attack within 6 months prior to enrollment
• congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to enrollment
• history of clinically significant (as determined by the treating physician) atrial arrhythmia
• any history of ventricular arrhythmia
• any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism .
• Uncontrolled hypertension (diastolic blood pressure \>90 mm Hg; systolic \>140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
• Taking medications that are known to be associated with Torsades de Pointes.

Sponsors & Collaborators

• Incyte Corporation: lead

Study Sites (42)

S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo

Alessandria, Italy

Location

Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI

Ancona, Italy

Location

Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni"

Ascoli Piceno, Italy

Location

Az.Ospedaliera S.G.Moscati

Avellino, Italy

Location

Azienda Ospedaliera - Papa Giovanni XXIII

Bergamo, Italy

Location

Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi

Bologna, Italy

Location

ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO

Cagliari, Italy

Location

Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"

Catania, Italy

Location

Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi

Ferrara, Italy

Location

Policlinico di Careggi

Florence, Italy

Location

Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"

Genova, Italy

Location

ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE

Lecce, Italy

Location

Unità Operativa Complessa - Medicina Generale - Sezione di Ematologia - Ospedale Versilia USL 12 Toscana

Lido di Camaiore, Italy

Location

Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST

Meldola, Italy

Location

U.O. di Ematologia- Ospedale dell'Angelo - Mestre

Mestre, Italy

Location

Ospedale Niguarda " Ca Granda"

Milan, Italy

Location

UO Ematologia - AOU Policlinico di Modena

Modena, Italy

Location

S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro

Novara, Italy

Location

Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2

Orbassano, Italy

Location

Università degli Studi di Padova - Ematologia ed Immunologia Clinica

Padua, Italy

Location

Ospedali Riuniti "Villa Sofia-Cervello"

Palermo, Italy

Location

S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo

Pavia, Italy

Location

Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia

Perugia, Italy

Location

Div. di Ematologia di Muraglia - CTMO Ospedale San Salvator

Pesaro, Italy

Location

U.O. Ematologia Clinica - Azienda USL di Pescara

Pescara, Italy

Location

Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza

Piacenza, Italy

Location

Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia

Pisa, Italy

Location

Dipartimento Oncologico - Ospedale S.Maria delle Croci

Ravenna, Italy

Location

Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"

Reggio Calabria, Italy

Location

Ospedale "Infermi"

Rimini, Italy

Location

Complesso Ospedaliero S. Giovanni Addolorata

Roma, Italy

Location

S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena

Roma, Italy

Location

U.O.C. Ematologia - Ospedale S.Eugenio

Roma, Italy

Location

Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia

Roma, Italy

Location

Università degli Studi - Policlinico di Tor Vergata

Roma, Italy

Location

UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche - AOU San Giovanni di Dio e Ruggi D'Aragona

Salerno, Italy

Location

U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"

Siena, Italy

Location

Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista

Torino, Italy

Location

Azienda U.L.S.S.9 - U.O. di Ematologia

Treviso, Italy

Location

Clinica Ematologica - Policlinico Universitario

Udine, Italy

Location

Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi

Verona, Italy

Location

ULSS N.6 Osp. S. Bortolo

Vicenza, Italy

Location

Related Publications (1)

• Martinelli G, Papayannidis C, Piciocchi A, Robustelli V, Soverini S, Terragna C, Marconi G, Lemoli RM, Guolo F, Fornaro A, Lunghi M, de Fabritiis P, Candoni A, Selleri C, Simonetti F, Bocchia M, Vitale A, Frison L, Tedeschi A, Cuneo A, Bonifacio M, Martelli MP, D'Ardia S, Trappolini S, Tosi P, Galieni P, Fabbiano F, Abbenante MC, Granier M, Zhu Z, Wang M, Sartor C, Paolini S, Cavo M, Foa R, Fazi P, Vignetti M, Baccarani M. INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia. Blood Adv. 2022 Mar 22;6(6):1742-1753. doi: 10.1182/bloodadvances.2021004821.

  PMID: 34649276 DERIVED

Related Links

• Gimema Foundation Website

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Michele Baccarani, Pr.

  Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2012
• First Posted: July 16, 2012
• Study Start: December 4, 2014
• Primary Completion: April 24, 2020
• Study Completion: September 30, 2021
• Last Updated: November 30, 2021

Record last verified: 2021-11

Locations

IT (42)