Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Philadelphia Chromosome

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Translocation, Genetic

Chromosome Aberrations

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Blinatumomab

Ponatinib

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I)

Ponatinib 45mg QD (reduction to 30mg QD after Induction) + low dose chemotherapy induction and consolidation I (Experimental Arm of Randomization I)

Molecular CR: End of therapy with indication for SCT (Standard Arm of Randomization II)

Molecular CR: No end of therapy with indication for SCT but and continuation with Imatinib/Ponatinib (per Randomization I), chemotherapy and Blinatumomab (Experimental Arm of Randomization II)

Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)

Imatinib

Patients with molecular failure or intermediate response receive one cycle Blinatumomab before SCT; Patients with molecular CR randomized to the experimental arm receive 3 cycles Blinatumomab + chemotherapy

Patients with molecular CR randomized to the standard arm have an indication for SCT; patients with molecular failure or intermediate response have an indication for SCT. SCT is not part of the trial.

Indication for stem cell transplantation

Nicola Goekbuget, MD

Fabian Lang, MD

Heike Pfeifer, MD

The current Standard of Care (SoC) in younger patients with Ph+ ALL is Imatinib in combination with low-dose chemotherapy, change of TKI in case of persistent MRD above 10-3 after consolidation I and indication for stem cell transplantation.

The EVOLVE trial aims to answer three questions challenging the current SoC:

Use of Ponatinib compared to Imatinib both in combination with low-dose chemotherapy and consolidation I (randomization I).

In MRD good responders: Omit end of therapy in primary care and indication for SCT but continue therapy with TKI, chemotherapy and Blinatumomab as additional antileukemic compound (randomization II).

In MRD poor responders: Omit indication for TKI change but give instead Blinatumomab followed by end of therapy in primary care and indication for SCT (non-randomized).

Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT

A Multicentre, Randomized Trial in Adults With de Novo Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia to Assess the Efficacy of Ponatinib Versus Imatinib in Combination With Low-intensity Chemotherapy, to Compare End of Therapy With Indication for SCT Versus TKI, Blinatumomab and Chemotherapy in Optimal Responders and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE)

Proportion of patients who achieve hematological and molecular remission or experience molecular failure

Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving ponatinib versus imatinib during induction therapy

Probability of continuous molecular remission at different time-points of Ponatinib versus Imatinib-based therapy

Measuring log-reduction (kinetic on MRD response) in patients with a Ponatinib versus Imatinib-based therapy

Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD in patients with blinatumomab in combination with Ponatinib versus Imatinib in patients with molecular persistence (molecular failure and MRD positivity below quantitative range) after consolidation 1

Probability of continuous MRD response and molecular remission and duration of molecular remission at different time-points in patients with molecular persistence (molecular failure and not quantifiable) receiving Blinatumomab in combination with Ponatinib versus Imatinib after consolidation 1

Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving Ponatinib or Imatinib in combination with Blinatumomab and chemotherapy

Probability of continuous MRD response and molecular remission and duration of molecular remission at different time-points in patients with Blinatumomab in combination with Ponatinib and chemotherapy or Imatinib and chemotherapy and rate of molecular relapse

Time to molecular remission measured by time-point of first achievement

Probability of overall survival up to 4 years from randomization I in patients with mo-lecular remission after consolidation 1 comparing a combination treatment of TKI, Blina-tumomab and chemotherapy versus EOT with indication for SCT

Rate of molecular complete remission at week 11 after consolidation with chemotherapy in combination with Ponatinb versus Imatinib

Deutsche Leukämie- & Lymphom-Hilfe

German Federal Ministry of Education and Research

Goethe University

Dr. Nicola Gökbuget

Angiogenesis Inhibitors

Endothelial Growth Factors

Mitogens

Jourik A Gietema, MD/PhD

Angiogenesis inhibitors and EGFR inhibitors not only have anti tumor activity but also modify physiological processes. This study evaluates effects on vascular function, endocrine function and metabolism. Changes in these parameters will be analysed for predictive value for treatment efficacy.

Background

In recent years, multiple new agents have been developed that inhibit angiogenesis and the epidermal growth factor receptor (EGFR) signalling pathway.

The cell signalling routes that are inhibited by these agents however are not only active in tumour formation but are also involved in physiological processes in normal tissue and organs. This means that these drugs do not only have an anti tumour effect but also modify several physiological processes that lead to side effects. Little is known about these side effects that generally are less severe than side effects of cytotoxic chemotherapy, but because targeted therapy is often administered for prolonged periods of time, these side effects can seriously affect quality of life.

Objectives

Primary objectives

1. To determine the characteristics, frequency and severity of vascular, metabolic and hormonal side effects of angiogenesis and EGFR inhibitors.

Secondary objectives

1. To investigate if steroid profile, indol profile, concentrations of catecholamines and metanephrines or thyroid antibodies change during treatment with angiogenesis and EGFR inhibitors.
2. To investigate if known biomarkers change during treatment.
3. To investigate whether vascular function changes during treatment with angiogenesis and EGFR inhibitors.
4. To determine if changes in skin autofluorescence and development of AGE's occur during treatment with angiogenesis and EGFR inhibitors.
5. To determine whether changes in factors mentioned under secondary objectives 1-4 are correlated with side effects of targeted therapy and/or response to angiogenesis and EGFR inhibitors.
6. To evaluate if polymorphisms in genes involved in pathways mentioned under 1-4 associate with toxicity and efficacy of angiogenesis and EGFR inhibitors.

Study design and population

This is a prospective, explorative observational cohort study in patients treated with angiogenesis or EGFR inhibitors. Concomitant chemotherapy, immunotherapy or radiotherapy is allowed. Patients must be 18 years or older at start of treatment and must be willing to give written informed consent.

Primary study parameters

Patients will be evaluated for vascular changes by measuring

* 24-hour ambulatory blood pressure
* nail fold capillary microscopy
* skin autofluorescence at 3 time points: before start of treatment, and after 3 and after 6 weeks of treatment. Patients will also be asked to measure their blood pressure at home twice a day, for 6 weeks. Metabolic and hormonal changes and investigation of biomarkers will be done by blood and urine analyses every 3 weeks for the first 3 months, every 6 weeks up to 6 months and every 3 months thereafter.

Changes in vascular, hormonal and metabolic status will be related to clinical side effects and to response to treatment.

Secondary study parameters

When clinically relevant differences in side effects and response to treatment are found among patients treated with the same agent, DNA analysis will be carried out to investigate if changes in candidate genes are related to these differences.

Burden and risks associated with participation, benefit and group relatedness

The minimal invasive tests will be performed during routine outpatient visits. As far as known no serious adverse events are linked to the described study procedures. With this study we hope to get insight into the characteristics, frequency, severity and underlying mechanisms of angiogenesis and EGFR inhibitor induced vascular, metabolic and hormonal side effects and to find usable surrogate markers for efficacy of treatment. Eventually, this may contribute to the early detection of vascular, metabolic and hormonal changes, to the design of intervention strategies for side effects and to better patient selection for angiogenesis and EGFR inhibition.

Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy

Mabtornib Protocol.Vascular, Metabolic and Hormonal Effects of Angiogenesis Inhibitors and Epidermal Growth Factor Receptor Inhibitors

Vascular function tests at baseline, after 3 and after 6 weeks of treatment, blood and urine measurements as long as treatment is continued.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT	NCT06061094	Philadelphia Ch...	Imatinib Ponatinib Blinatumomab Indication for ...	18 Years - 65 Years	Goethe University
Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT	NCT06061094	Philadelphia Ch...	Imatinib Ponatinib Blinatumomab Indication for ...	18 Years - 65 Years	Goethe University
Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy	NCT00657098	Metastatic Mali...		18 Years -	University Medical Center Groningen
Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy	NCT00657098	Metastatic Mali...		18 Years -	University Medical Center Groningen

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