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Report for Clinical Trial NCT01641107

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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.

NCT01641107 Philadelphia Positive BCR-ABL Positive Acute Lymphoblastic Leukemia
MeSH: Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO: Leukemia Lymphoid leukemia

1 Interventions

Name: Ponatinib

Description: 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.

Type: Drug

Ponatinib


Primary Outcomes

Description: 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).

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

Time: At 6 months from study entry.

Secondary Outcomes

Description: 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

Measure: The rate of Complete Hematological Response (CHR).

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

Description: 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: Complete (CCgR) if Ph pos 0 Partial (PCgR) if Ph pos 1-34% Minor (mCgR) if Ph pos 35-65% 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.

Measure: The rate of complete Cytogenetic Response (CgR).

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

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

Measure: Duration of Complete Cytogenetic Response (CCgR).

Time: After four years from study entry.

Description: 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.

Measure: The rate of Complete Molecular Response (CMoIR).

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

Description: 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.

Measure: The rate of major molecular response.

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

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

Measure: Duration of Complete molecular response (CMR).

Time: After four years from study entry.

Measure: Type and number of BCR-ABL kinase domain mutations.

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

Measure: Percentage of relationships between the response and the biomarkers.

Time: At six months from study entry.

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

Measure: Event Free Survival.

Time: After four years from study entry.

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

Measure: Overall survival

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

Measure: Failure Free Survival

Time: After four years from study entry.

Measure: Rate of Rate of side effects, adverse events and serious adverse events.

Time: After four years from study entry.

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 T315I

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. --- T315I ---



HPO Nodes


HPO:
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Lymphoid leukemia