Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Translocation, Genetic

Chromosome Aberrations

Chronic Graft Versus Host Disease

Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Ponatinib

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Ponatinib (Iclusig®) : Tyrosine Kinase Inhibitor (BCR-ABL); oral (tablets) : 30mg/day during 6 months (induction phase); Takeda \& Incyte Biosciences.

Imatinib (either Glivec® or any generic form) : Tyrosine Kinase Inhibitor (BCR-ABL, ABL, KIT and PDGFRA receptor tyrosine kinases); oral : 400 mg/day during at least 30 months (then, depending of MR4.5)

30mg/day; 6 months. Dose adaptation procedures are planned in case of toxicity.

400 mg/day; at least 30 months (M7 to M36), then depending of MR4.5 . Dose adaptation procedures are planned in case of toxicity.

Imatinib

Franck-Emmanuel NICOLINI, MD

The investigators hypothesize that, in newly diagnosed de novo chronic phase CML patients, an induction treatment with ponatinib for 6 months should increase the rate of patients reaching a stable MR4.5 allowing cessation of imatinib treatment.

The investigators proposal is to conduct a multicenter, Phase II trial to evaluate the safety, clinical and biological activity of an induction treatment with ponatinib for 6 months, followed by a consolidation treatment with imatinib in newly diagnosed de novo chronic phase CML patients.

TREATMENT PLAN :

All eligible patients will be treated:

* During the induction Phase (Month 1 to Month 6) with ponatinib (30mg/day) single agent; then
* During the consolidation Phase (Month 7 to Month 36) with imatinib (400mg/day) single agent; then
* From M36 :

  * Patients with stable MR4.5 (i.e. since at least 2 years) will enter in the TFR phase and will stop imatinib treatment. Thereafter, in case of MMR loss, imatinib will be re-introduced as per investigator judgement (including for dose).
  * Patients without stable MR4.5 will continue imatinib treatment until stable MR4.5, or M60, PD, death, withdrawal of consent or overall trial completion. Such patients will be allowed to enter into the TFR phase as soon as a stable 2-year MR4.5 is reached: however, they will be considered as a failure for the primary endpoint analysis.

STATISTICS :

A total of 170 patients will be enrolled in this study.

According to a Fleming design, with a P0=20% as minimal efficacy rate and P1=30% as an expected target, 156 patients should be enrolled, assuming an unilateral type I error alpha of 5% and 90% power. At the time of analysis, if at least 40 successes are observed among the 156 evaluable patients, the treatment will be considered as interesting for further investigation in this indication. Considering that some patients may withdraw their consent before 36 months (about 10%), the investigators plan to enrol 170 patients in total.

DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. Serious adverse event (SAE) and Adverse Event of Specific Interest (AESI) reporting will be also paper-based by e-mail and/or Fax.

The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase

A Multicentre, Open-label Phase II Trial Evaluating the Safety and Efficacy of Ponatinib Induction Followed by Imatinib Maintenance in Adult Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) ≤ 65 Years

Rate of patients reaching a stable MR4.5 (BCR-ABL (IS) ≤0.0032% with at least 32,000 copies of ABL) for ≥ 2 years at Month 36 after initiation of ponatinib.

For all patients : Rate of patients with MR4.5; MR4.0 and MMR at 1, 2, 3, 6, 9, 12, 24 months after ponatinib initiation

For all patients : Rate of patients with a BCR-ABL/ABL (IS) ≤ 10% and rate of patients with CCyR (or its molecular equivalent, BCR-ABL/ABL (IS) ≤ 10%) at 3 and 6 months after ponatinib initiation.

For all patients : Time to MR4.5, MR4.0 or MMR following ponatinib initiation

For all patients : Duration of MR4.5, MR4.0 or MMR

For all patients : Progression Free survival

For patients reaching TFR criteria and following imatinib cessation: Rate of successful TFR (patients sill with MR4.5) at 3, 6, 9, 12 and 24 months after imatinib cessation

For patients reaching TFR criteria and following imatinib cessation: Duration of TFR after imatinib cessation.

For patients reaching TFR criteria and following imatinib cessation: OS after imatinib cessation

For patients reaching TFR criteria and following imatinib cessation: PFS after imatinib cessation

For patients reaching TFR criteria and following imatinib cessation: Event-free survival according ELN recommendations

For patients reaching TFR criteria and following imatinib cessation: Rate of TKI-withdrawal syndrome after Imatinib cessation

For patients reaching TFR criteria and following imatinib cessation: Rate of MMR, MR4.0 and MR4.5 recovery in case of imatinib re-introduction (

* Hematologic and non-hematologic AEs graded according to the NCI CTCAE v5.0
* Incidence of arterial thrombotic events during the induction phase and during the consolidation phase.

Evolution of Quality of life according to QLQ-CML24 questionnaire.

Evolution of Quality of life according to QLQ-C30 questionnaire.

Plasma concentrations of ponatinib over the 6 months of the induction period.

Compliance to ponatinib and imatinib as evaluated using the Morisky medication adherence scale questionnaire

Centre Leon Berard

Immune System Diseases

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Lymphoma

Acquired Immunodeficiency Syndrome

HIV Infections

HIV Seropositivity

Burkitt Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Communicable Diseases

Epstein-Barr Virus Infections

Virus Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Blood-Borne Infections

Sexually Transmitted Diseases

Sexually Transmitted Diseases, Viral

Lentivirus Infections

Retroviridae Infections

RNA Virus Infections

Genital Diseases

Urogenital Diseases

Syndrome

Immunologic Deficiency Syndromes

Lymphosarcoma

B-cell Lymphoma

Anti-Infective Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Etoposide

Cytarabine

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Methotrexate

Rituximab

Vincristine

Melphalan

Prednisolone

Immunomodulating Agents

Etoposide phosphate

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Experimental treatment consists of an induction phase followed by a consolidation or intensified phase according to tumor response.

* dd -2 to 1: Methylprednisolone
* dd 0-1, Cyclophosphamide, associated on day 0 with Vincristine
* dd 2, Rituximab
* dd 7, Methotrexate
* dd 14, Rituximab
* dd 15, Etoposide
* dd 21, Methotrexate
* dd 29, Rituximab and Doxorubicin
* dd 36, Rituximab and VCR

At the end of this induction phase, subsequent treatment will be performed according to the objective response:

1. pts in CR: consolidation phase followed by bulky site irradiation
2. pts in PR: consolidation phase followed by BEAM conditioning regimen supported by ASCT and bulky irradiation
3. pts with SD after induction or PD during or after induction: intensification phase followed by BEAM conditioning regimen supported by ASCT and bulky irradiation

Induction Phase

* dd 1-2: cytarabine twice a day
* dd 3 and 11: rituximab
* dd 11-13: leukapheresis for PBPC collection.

Consolidation Phase (on day +50)

1. One or two courses of R-IVAC or R-ICE chemoimmunotherapy regimen, every three weeks as debulking.
2. CTX (dd 1) associated with rituximab on dd 3 and 10, followed by PBPC collection (dd 11-13);
3. AraC every 12 hours for four days (dd -5 to -2) supported by reinfusion of CD34+ cells (dd 0), rituximab infusion (dd -1 and +11) and second in-vivo purged PBPC collection (if needed).

Intensification phase

BCNU on dd 1; VP-16 every 12 hours on dd 2-5 and araC every 12 hours on dd 2-5; melphalan on dd 6, followed by the reinfusion of CD34+ cells

BEAM conditioning

At the end of the whole program, patients will be evaluated for involved-field irradiation with 6-10 MeV photons and a dose of 36 Gy (2 Gy/d, five fractions a week). Three subgroups of patients will be considered for radiotherapy

Consolidation radiotherapy

Andrés JM Ferreri, MD

This is a multicenter,open-label trial to evaluate activity and safety of the investigational intensive in HIV+ patients with Burkitt's lymphoma.

Experimental treatment consists of an induction phase followed by a consolidation or intensified phase according to tumor response.

Until recently, the immuno-compromised state of patients with concomitant HIV/AIDS and BL was thought to limit the ability to administer intensive chemotherapeutic regimens due to infection rate. However, the advent of highly active antiretroviral therapy (HAART) and evidence in diffuse large B-cell lymphomas that HIV-positive patients can tolerate standard chemotherapeutic regimens with improved outcomes have led investigators to treat HIV-positive patients with the same intensive chemotherapy regimens used to treat immuno-competent patients. Data suggest that these current approaches, along with supportive care, may result in improved patient outcomes, similar to those in the immuno-competent patient population.

The activity of feasibility of the proposed program will be assessed in HIV+ patients with Burkitt lymphoma with the aim to improve tolerability, minimize source consuming and supporting treatment and redu ce late sequels. Available combinations in this setting are really source demanding and toxic combinations showing high rates of septic complication and a treatment-related mortality of near 20%.

Short Term Intensified Chemo-immunotherapy in HIV-positive Patients With Burkitt Lymphoma

Phase II Study on Safety and Activity of a Short Term Intensified Chemo-immunotherapy Combination in HIV-positive Patients Affected by Burkitt Lymphoma

Objective lymphoma response achieved after the induction phase of the experimental treatment.

Assessment of incidence of grade 4 AE during experimental treatment (induction, consolidation and intensification phases as well as conditioning and autologous stem cell transplantation (if indicated)

Participants who will not achieve a complete or partial response after induction and consolidation phases will be referred to intensification phase, which will be followed by BEAM + ASCT. These patients will be assess for tolerabbility and AE during these therapeutic phases.

Participants will be assessed by conventional exams to define complete remission rate after the whole experiemntal program; that is after consolidation phase for patients who achieved complete remission after induction phase, after BEAM + ASCt for patients who achieved partial response after induction phase, and after intensification phase for patients who did not achieve an objective response after induction phase.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase	NCT04070443	Philadelphia Ch... BCR-ABL Positiv...	Ponatinib Imatinib	18 Years - 65 Years	Centre Leon Berard
Short Term Intensified Chemo-immunotherapy in HIV-positive Patients With Burkitt Lymphoma	NCT01516593	HIV Burkitt's Lymph...	Induction Phase Consolidation P... Intensification... BEAM conditioni... Consolidation r...	18 Years - 60 Years	IRCCS San Raffaele
Short Term Intensified Chemo-immunotherapy in HIV-positive Patients With Burkitt Lymphoma	NCT01516593	HIV Burkitt's Lymph...	Induction Phase Consolidation P... Intensification... BEAM conditioni... Consolidation r...	18 Years - 60 Years	IRCCS San Raffaele
Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase	NCT04070443	Philadelphia Ch... BCR-ABL Positiv...	Ponatinib Imatinib	18 Years - 65 Years	Centre Leon Berard

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