Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Ponatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Administration of ponatinib after allo-SCT transplant in FLT3-ITD AML patient

Ponatinib 30 MG

Recent advances in acute myeloid leukemia (AML) have been characterized by a better understanding of disease biology. As such, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have been recognized as conferring a poor prognosis. The FLT3-ITD molecular mutation is observed in about one-quarter of patients diagnosed with AML. Patients presenting with this abnormality are referred for early allogeneic stem-cell transplantation (allo-SCT). However, some data suggest that FLT3-ITD remains associated with a poor prognosis even after allo-SCT because of higher risk of relapse and strategies for preventing relapse in the post-transplant setting are required (Hu et al, Expert Rev Hematol, 2014). For example, in a large cohort of patients (Brunet et al, JCO, 2012), the incidence of relapse for FLT3-ITD AML patients after allo-SCT was 30% at 2-years, significantly higher compared to FLT3-ITD negative patients (p=0.006).

Ponatinib (Iclusig®) is an orally available, tyrosine kinase inhibitor with a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). In vitro activity of ponatinib in AML has been already demonstrated (Gozgit et al, Mol Cancer Ther, 2011; Smith et al, Blood 2013). If some trials are on-going to test ponatinib alone or in combination with chemotherapy in FLT3-ITD AML (Clinical.trials.gov), no study is dedicated to the use of ponatinib in the post-transplant setting in order to prevent relapse in these patients.

The main goal of this study will be to determine the maximal tolerated dose (MDT) of ponatinib after allo-SCT in FLT3-ITD AML patients, then to investigate the efficacy of ponatinib in a larger cohort of patients

Study of Ponatinib (Iclusig) for Prevention of Relapse After Allogeneic Stem Cell Transplantation (Allo-SCT) in FLT3-ITD AML Patients

Phase 2 Study of Ponatinib (Iclusig) for Prevention of Relapse After Allogeneic Stem Cell Transplantation (Allo-SCT) in FLT3-ITD AML Patients: the PONALLO Trial."

time interval from the graft (day 0) until the date of last follow-up or death

time interval from the date of the graft (day 0) until the date of last follow-up, death or relapse

incidence of mortality due to all causes except relapse after transplant, considering that cause of death for patients having relapsed but dying from another cause is relapse

an immunophenotype of PB lymphocytes will be performed by flow cytometry at +3, +6, +9 and +12 months post-transplant to study the reconstitutions of CD3, CD4 and CD8 T cells, B and NK cells. The results will be expressed as absolute counts (Giga/L). We want to establish the potential influence of ponatinib on the reconstitution of these cells

Donor peripheral blood and CD3 T cells chimerism will be studied using molecular markers and RT-PCR at day +30, +60, +90, and +6, +12 months post-transplant. We want to establish the potential influence of ponatinib on the chimerism post-transplant.

Versailles Hospital

investigator coordinator

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Trametinib

Trametinib 0.5mg PO q daily Ponatinib 15mg PO q daily

Trametinib 1.0 mg PO q daily Ponatinib 15mg PO q daily

Trametinib 1.5 mg PO q daily 15mg PO q daily

Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily

Trametinib 2 mg PO q daily Ponatinib 30mg PO q daily

Maximum tolerated dose as established in Phase I portion

Trametinib 0.5 mg

Trametinib 1 MG

Trametinib 1.5 MG

Trametinib 2 mg

Ponatinib 15 MG

Kathryn Arbour, MD

The purpose of this study is to evaluate the safety of the combination of ponatinib and trametinib as well as the most appropriate dosages of the combination.

Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer

A Phase 1 Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer

In the Phase I portion of the study, a standard 3+3 design will be used to find the maximum tolerated dose.

In the Phase II portion of the study, RECIST criteria 1.1 will evaluate the overall response rate. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Memorial Sloan Kettering Cancer Center

No participants were enrolled in "Phase I: Dose Level -3", "Phase I: Dose Level -2", "Phase I: Dose Level -1" and "Phase II" arms

Trametinib 0.5mg PO q daily Ponatinib 15mg PO q daily

Trametinib 0.5 mg: 0.5mg PO q daily

Ponatinib 15 MG: 15mg PO q daily

Phase I: Dose Level -3

Trametinib 1.0 mg PO q daily Ponatinib 15mg PO q daily

Trametinib 1 MG: 1.0 mg PO q daily

Ponatinib 15 MG: 15mg PO q daily

Phase I: Dose Level -2

Trametinib 1.5 mg PO q daily 15mg PO q daily

Trametinib 1.5 MG: 1.5mg PO q daily

Ponatinib 15 MG: 15mg PO q daily

Phase I: Dose Level -1

Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily

Trametinib 2 mg: 2 mg PO q daily

Ponatinib 15 MG: 15mg PO q daily

Phase I: Dose Level 1

Trametinib 2 mg PO q daily Ponatinib 30mg PO q daily

Trametinib 2 mg: 2 mg PO q daily

Ponatinib 30 MG: 30mg PO q daily

Phase I: Dose Level 2

Maximum tolerated dose as established in Phase I portion

Trametinib 2 mg: 2 mg PO q daily

Ponatinib 15 MG: 15mg PO q daily

Phase II

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

No participants were enrolled in "Phase I: Dose Level -3", "Phase I: Dose Level -2", "Phase I: Dose Level -1" and "Phase II" arms due to cardiovascular events observed at Dose Level 2

Dr. Kathryn Arbour

Dose Level 1: Trametinib 2 mg PO q daily Ponatinib 15mg PO q daily Dose Level 2: Trametinib 2mg, Ponatinib 30mg

Phase I: Dose Level 1 and Dose Level 2

Maximum Tolerated Dose of Ponatinib, Phase I

Cardiovascular events were observed at Dose Level 2 and continued exploration of other dose levels did not proceed.

Overall Response Rate

Overall Study

Symptoms and General Pathology

Digestive System Diseases

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Sunitinib

Imatinib Mesylate

patients with primary c-KIT mutations and with either no detectable or non-exon13-secondary mutations (as measured by plasma sequencing); failure of imatinib treatment (only) Treatment with oral ponatinib 30MG (milligram) daily until progression or intolerable side effects.

GIST patients with primary c-KIT mutations and secondary c-KIT mutations in Exon 13; failure of imatinib treatment (only) Treatment with oral ponatinib 30MG daily until progression or intolerable side effects.

GIST patients with KIT-mutations and treatment failure of imatinib, sunitinib and regorafenib.

Treatment with oral ponatinib 30MG daily until progression or intolerable side effects.

Ponatinib: once-daily oral dose of 30mg. A cycle of treatment is defined as 28 days. Doses may be reduced to manage drug-related adverse events and may be re-escalated once events resolve.

Johanna Falkenhorst

Sebastian Bauer, Prof. Dr.

This is a non-randomized, open-label, multicenter phase 2 study to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable GIST after prior failure or intolerability of imatinib. Patients will be enrolled into 1 of 2 cohorts based on absence (Cohort A) or presence (Cohort B) of KIT exon 13 resistance mutations as measured by liquid biopsy. A third cohort (Cohort C) will include patients who have received all approved lines of TKI treatments (imatinib, sunitinib and regorafenib).

Primary Objective

* To assess clinical benefit of ponatinib in patients with KIT or PDGFRA mutant GIST defined as clinical benefit rate (CBR), which is the composite of complete response (CR), partial response (PR) and stable disease (SD) at ≥16 weeks after start of treatment per modified response evaluation criteria in solid tumors (modified RECIST 1.1 \[Demetri et al., 2013\]) as a measure of disease control
* Two cohorts for second-line patients will be used: Cohort A: patients with secondary resistance mutations in other exons or no resistance mutations (as measured by liquid biopsy in circulating DNA); Cohort B: patients with evidence of secondary resistance mutations in exon 13 as assessed on progressing lesions or in circulating DNA
* One additional Cohort (Cohort C) will include heavily pretreated patients (failure of at least all approved lines of therapy) regardless of secondary mutation Secondary Objectives
* To assess progression-free survival (PFS) in each cohort and in the total patient population
* To assess objective response rate (ORR) in each cohort and in the total patient population
* To assess overall survival (OS) in each cohort and in the total patient population
* To evaluate the safety and tolerability of ponatinib in the total patient population
* To assess Quality of Life (QoL) Exploratory Objectives
* To assess limited elements of pharmacokinetics (PK) in the total patient population
* To explore the relationship between GIST genotype and CBR with ponatinib
* To explore the feasibility of detecting mutations in KIT and possibly other cancer-related genes using circulating nucleic acids derived from blood samples
* To explore the usefulness of "liquid biopsies" to predict treatment response and development of resistance
* To assess duration of follow-up treatment

Primary Endpoint

* CBR consisting of CR+PR+SD by modified RECIST 1.1 (Demetri et al., 2013) at 16 weeks in patients with imatinib-resistant GIST (KIT-mutant) with other or no resistance mutations (Cohort A) and secondary resistance mutation in exon 13 (Cohort B) Secondary Endpoints
* PFS in each cohort and in the total patient population
* ORR (CR + PR) in each cohort and in the total patient population
* OS in each cohort and in the total patient population
* Safety and tolerability of ponatinib
* QoL
* CBR of Cohort C Exploratory Endpoints
* Correlation of plasma levels of ponatinib and response
* Molecular genetic features of GIST at baseline and after treatment with ponatinib
* Correlation of tumor DNA from available paraffin tissue with genotypes of plasma sequencing ("liquid biopsies") and correlation of plasma genotype with treatment response, resistance and duration of follow-up treatment

POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Following Failure or Intolerance of Prior Therapy With Imatinib

CBR consisting of CR+PR+SD by modified RECIST 1.1 (Demetri et al., 2013) at 16 weeks in patients with imatinib-resistant GIST (KIT-mutant) with other or no resistance mutations (Cohort A) and secondary resistance mutation in exon 13 (Cohort B)

Assessment in each cohort and in the total patient population

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire)

Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Ponatinib (Iclusig) for Prevention of Relapse After Allogeneic Stem Cell Transplantation (Allo-SCT) in FLT3-ITD AML Patients	NCT03690115	Leukemia, Myelo...	Ponatinib 30 MG	18 Years - 70 Years	Versailles Hospital
Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer	NCT03704688	Non Small Cell ... KRAS Gene Mutat...	Trametinib 0.5 ... Trametinib 1 MG Trametinib 1.5 ... Trametinib 2 mg Ponatinib 15 MG Ponatinib 30 MG	19 Years -	Memorial Sloan Kettering Cancer Center
POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST	NCT03171389	GIST, Malignant KIT Exon 13 Mut... KIT Gene Mutati...	Ponatinib 30 MG	18 Years -	Universität Duisburg-Essen
POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST	NCT03171389	GIST, Malignant KIT Exon 13 Mut... KIT Gene Mutati...	Ponatinib 30 MG	18 Years -	Universität Duisburg-Essen

Spots Global Cancer Trial Database for ponatinib 30 mg