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Philadelphia PositivePhase 2LAL1811NCT01641107

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

A Phase 2 study testing Ponatinib in people with Philadelphia Positive and BCR-ABL Positive, run by Incyte Corporation at 42 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ponatinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
44 participants
Where
42 sitesItaly
Study dates
4 Dec 2014to 30 Sep 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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).
Show all 24Show fewer
  • 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.
  • Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib.
  • Creatinine level > 2.5mg/dl or Glomerular Filtration Rate (GFR) < 20 ml/min or proteinuria > 3.5 g/day.
  • Impairment of gastrointestinal (GI) function, or a GI disease that may significantly alter the absorption of study drugs (e.g. rare hereditary problems of galactose intolerance , the Lapp lactase deficiency or glucose-galactose malabsorption, severe malabsorption syndrome, or extended small bowel resection).
  • Patients who are currently receiving treatment with any of the medications listed in Appendix E if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT.
  • Patients who have received any investigational drug ≤ 4 weeks.
  • Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
  • Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Ponatinib). Post menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 4 months following discontinuation of study drugs.
  • Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
  • Patients unwilling or unable to comply with the protocol.

Trial locations and contacts

42 sites in 1 country.

42 sites in 1 country

Italy42 sites

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

    Alessandria

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

    Ancona

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

    Ascoli Piceno

  • Az.Ospedaliera S.G.Moscati

    Avellino

  • Azienda Ospedaliera - Papa Giovanni XXIII

    Bergamo

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

    Bologna

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

    Cagliari

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

    Catania

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

    Ferrara

  • Policlinico di Careggi

    Florence

  • Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"

    Genova

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

    Lecce

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

    Lido di Camaiore

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

    Meldola

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

    Mestre

  • Ospedale Niguarda " Ca Granda"

    Milan

  • UO Ematologia - AOU Policlinico di Modena

    Modena

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

    Novara

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

    Orbassano

  • Università degli Studi di Padova - Ematologia ed Immunologia Clinica

    Padova

  • Ospedali Riuniti "Villa Sofia-Cervello"

    Palermo

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

    Pavia

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

    Perugia

  • Div. di Ematologia di Muraglia - CTMO Ospedale San Salvator

    Pesaro

  • U.O. Ematologia Clinica - Azienda USL di Pescara

    Pescara

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

    Piacenza

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

    Pisa

  • Dipartimento Oncologico - Ospedale S.Maria delle Croci

    Ravenna

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

    Reggio Calabria

  • Ospedale "Infermi"

    Rimini

  • Complesso Ospedaliero S. Giovanni Addolorata

    Roma

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

    Roma

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

    Roma

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

    Roma

  • Università degli Studi - Policlinico di Tor Vergata

    Roma

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

    Salerno

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

    Siena

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

    Torino

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

    Treviso

  • Clinica Ematologica - Policlinico Universitario

    Udine

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

    Verona

  • ULSS N.6 Osp. S. Bortolo

    Vicenza

Other trials in Italy

About this study

Official title: Front-line Treatment of Philadelphia Positive/BCR-ABL Positive Acute Lymphoblastic Leukemia With Ponatinib, a New Potent Tyrosine Kinase Inhibitor.

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.

Read the detailed description

This is a multi-center, phase 2, single arm unblinded trial of oral Ponatinib in patients with Ph+ Acute Lymphoblastic Leukemia. 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. Then a patient can be discontinued in the following situation:

  • at the end of first course (6 weeks), in case of lack of CHR;
  • at the end of third course (18 weeks), in case of lack of CCgR;
  • any time in case of loss of CHR or CCgR.

If they remain on therapy after 48 weeks, they will be able to continue treatment during the extension phase of the study, if it is of interest of the patient, or they will be allowed to receive any treatment that is in their interest. For all the patients remaining on trial, response, outcome and toxicity will be followed for the subsequent 24 months.The 6-weeks periodicity must be rigidly respected, irrespective of the temporary discontinuation of study drug (eg, if a patient will take Ponatinib only for 4 weeks and will remain off-treatment for the subsequent two weeks because of AE, when the 7th week begins this patient will restart Ponatinib as a second course, as per protocol). Prednisone (P) will be administered to all patients for 7-14 days, before Ponatinib, so as to make it possible to wait for the results of cytogenetic and molecular tests, and to evaluate the response to P alone, hence for another 21 days. Intrathecal therapy (IT) with MTX/AraC/DEX is mandatory, every 28 days, in patients without clinical-cytologic evidence of meningeal involvement. In patients with CNS disease, IT is performed twice weekly until a complete clearance of cerebrospinal fluid blast cells is achieved, hence once weekly for 4 weeks, hence once monthly.

Being tested
Ponatinib
Keywords
Ph+, BCR-ABL+, ALL, Ponatinib, stem cell transplantation
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PonatinibDrug

    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.

Study groups in NCT01641107
Study groupRoleWhat they receive
PonatinibExperimentalNot described
Receives: Drug: Ponatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: At 6 months from study entry.

Secondary outcomes (12)

  1. The rate of Complete Hematological Response (CHR).

    CHR requires that all of the following are present:

    • Bone marrow with less than 5% blast cells
    • Peripheral blood differential without blasts
    • PMN ≥ 1.5 x 109/L
    • PLT ≥ 100 x 109/L
    • No evidence of extramedullary involvement from leukemia

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

  2. The rate of complete Cytogenetic Response (CgR).

    CgR is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases:

    1. Complete (CCgR) if Ph pos 0
    2. Partial (PCgR) if Ph pos 1-34%
    3. Minor (mCgR) if Ph pos 35-65%
    4. Minimal or none (min/none CgR) if Ph pos > 65% If only interphase FISH data are available, the response can be defined only as non-complete or complete - to be complete by FISH, it is required that less than 1% of nuclei (minimum number 200) have a positive signal.

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

  3. Duration of Complete Cytogenetic Response (CCgR).

    Duration of CCgR is measured by the date of the achievement of CCgR to the date of CCgR loss.

    Measured: After four years from study entry.

  4. The rate of Complete Molecular Response (CMoIR).

    Molecular response is classified as:

    • Complete if by RT-Q-PCR the BCR-ABL: ABL ratio is below 0.01, with a sensitivity of at least 30,000 molecules of ABL.

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

  5. The rate of major molecular response.

    Molecular response (MR) is classified as:

    • Major (MMolR) if by RT-Q-PCR the BCR-ABL: ABL ratio is lower than 0.10, with a sensitivity of at least 30,000 molecules of ABL.

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

  6. Duration of Complete molecular response (CMR).

    Duration of CMR is measured by the date of the achievement of CMR to the date of CMR loss.

    Measured: After four years from study entry.

  7. Type and number of BCR-ABL kinase domain mutations.

    Measured: At the end of the study. At four years after enrollment of first patient.

  8. Percentage of relationships between the response and the biomarkers.

    Measured: At six months from study entry.

  9. Event Free Survival.

    Events are induction failure, relapse and death whichever comes first.

    Measured: After four years from study entry.

  10. Overall survival

    Overall survival is measured in all patients from the data of enrolment to the date of death, by any causes.

    Measured: At the end of study. After four years from enrolment.

  11. Failure Free Survival

    Measured: After four years from study entry.

  12. Rate of Rate of side effects, adverse events and serious adverse events.

    Measured: After four years from study entry.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jul 2012 (estimated)
  2. Study start4 Dec 2014
  3. Primary completion24 Apr 2020
  4. Study completion30 Sep 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
44 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01641107
Sponsor's protocol ID
LAL1811
Other IDs
2012-002761-35
Acronym
LAL1811
Status last verified
Nov 2021
First submitted
12 Jul 2012
Last updated
30 Nov 2021
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 34649276

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ponatinib in people with Philadelphia Positive and BCR-ABL Positive, run by Incyte Corporation at 42 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 42 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of patients who are in Complete Hematological Response (CHR). (time frame: At 6 months from study entry.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01641107, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2021.

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