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Waldenstrom Macroglobulinemia

Neoplasms, Plasma Cell

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Dexamethasone

Cyclophosphamide

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Bortezomib

Dexamethasone acetate

BB 1101

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Alkylating Agents

Antineoplastic Agents, Immunological

Glucocorticoids

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Induction experimental arm (Arm B):

Cycle 1:

Bortezomib 1.6 mg/m2 s.c. Day 1,8,15; Dexamethasone 20 mg p.o. Day 1; Rituximab 375 mg/m2 i.v. Day 1; Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5

Cycle 2-6:

Bortezomib 1.6 mg/m2 s.c. Day 1,8,15; Dexamethasone 20 mg p.o. Day 1; Rituximab 1400 mg absolute sc Day 1; Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5; Repeat day 29.

Induction standard arm (Arm A)

Cycle 1:

Dexamethasone 20 mg p.o. Day 1; Rituximab 375 mg/m2 i.v. Day 1; Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5;

Cycle 2-6:

Dexamethasone 20 mg p.o. Day 1; Rituximab 1400 mg absolute sc Day 1; Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5; Repeat day 29.

Dexamethasone, Rituximab, Cyclophosphamide

Dexamethasone, Rituximab, Cyclophosphamide, Bortezomib

Martin Dreyling, MD

Veronique Leblond, MD

Pierre Morel, MD

Garcia Sanz, MD

Maria da Silva, MD

Meletios Dimopoulos, MD

Eva Kimby, MD

Roman Hajek, MD

Wolfram Klapper, MD

Sylvie Chevret

Christian Buske, MD

In Waldenström macroglobulinemia (WM) conventional chemotherapy induces only low CR rates and responses of short duration compared to other indolent lymphomas. Thus innovative approaches are needed which combine excellent activity and tolerability in patients with WM, who are mostly of advanced age. The immunochemotherapy DRC (dexamethasone, rituximab, cyclophosphamide) was shown to be highly effective in patients with WM without inducing major hematological toxicities. On the other hand the proteasome inhibitor Bortezomib showed substantial activity as a single agent in WM with only very few side effects when given in a weekly schedule. Based on these observations it is the aim of this study to test whether the efficacy of the well tolerated DRC regime can be further improved by adding Bortezomib.

Waldenström's macroglobulinemia (WM) is defined by a bone marrow infiltration by lymphoplasmacytic cells and the presence of a monoclonal immunoglobulin (Ig) M gammopathy in the peripheral blood. The clinical understanding of the disease has been greatly improved by the identification of internationally recognized criteria for initiating therapy, the description of an international prognostic index for patients requiring a first-line therapy and the definition of response criteria. These criteria are mainly based on the evolution of serum IgM concentration. However, delayed IgM monoclonal protein responses may cause important difficulties in response assessment. In addition, discrepancies between the kinetics of serum M protein reduction and the clearance of monoclonal B-cells from the bone marrow have been reported. Despite continuing advances in the therapy of WM, the disease remains incurable with a median survival of 5 to 8 years from the time of diagnosis thereby necessitating the development and evaluation of novel treatment approaches.

Efficacy of First Line DRC +/- Bortezomib for Patients With Waldenström's Macroglobulinemia

Efficacy of First Line Dexamethasone, Rituximab and Cyclophosphamide (DRC) +/- Bortezomib for Patients With Waldenström's Macroglobulinemia

PFS will be calculated from the date of inclusion/randomisation to the following events: the date of progression and the date of death if it occurred earlier. In the absence of progression and death, PFS duration will be censored at the stopping date or the date of last follow-up.

The response rates (CR,VGPR, PR, MR) and overall response rate (CR, VGPR, PR, MR) are evaluated 4 weeks after the end of induction treatment.

Best response is determined in the time interval from the start of induction therapy to end of follow-up.

Time to best response is defined as the time from the start of induction to best response the patient achieves (CR, VGPR, PR, MR).

Time to first response is defined as the time from the start of induction to first response (MR, PR, VGPR or CR).

Time to treatment failure (TTF) is defined as the time of randomization to discontinuation of therapy for any reason including death from any cause, progression, toxicity or add-on of new anti-cancer therapy. Patients alive without treatment failure are censored at the latest tumor assessment date.

Remission duration will be calculated in patients with response (CR, VGPR, PR, MR) to induction from end of induction to the date of progression, relapse or death from any cause. Patients alive without progression and relapse will be censored at the latest tumor assessment date or the stopping date.

Cause specific survival is defined as the period from the induction randomization to death from lymphoma or lymphoma related cause; death unrelated to WM is considered as a competing event.

Overall survival is defined as the period from the induction randomization to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.

Centre Hospitalier de Lens (Co-Sponsor)

University of Ulm

Prof. Dr. med. Christian Buske

Respiratory Tract (Lung and Bronchial) Diseases

Nervous System Diseases

Symptoms and General Pathology

Behaviors and Mental Disorders

Lung Neoplasms

Neurobehavioral Manifestations

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Study participants with advanced-stage lung cancer.

Surveys about symptoms, mood, and quality of life.

Questionnaire

Automated telephone system call once a week during therapy, rating of severity of symptoms and daily life interference done with numeric key pad. Post therapy is complete, a call every two weeks for up to six months.

Telephone Interactive System

For participating patients, 3 additional tablespoons of blood drawn at the beginning of each chemotherapy treatment (before treatment starts) and at the beginning of each cycle of treatment.

Blood Samples

Xin Shelley Wang, MD

Primary Objectives:

* To compare the severity of symptoms, their impact on affective and health-related functional status, and symptom interference among patients with advanced-stage lung cancer following initiation of chemotherapy by disease status, tumor response to chemotherapy, and adequacy of symptom management.
* To examine the relationship of disease-related and treatment-related physical symptoms to affective impairment and the patient's reported symptom interference and functional impairment.
* To compare symptom severity, adequacy of symptom management, and interference with affective status and health-related function by patient's minority status.
* To explore the serum level of inflammatory cytokines during chemotherapy among lung cancer patients.
* To measure DNA repair capacity (DRC) in lymphocyte cultures of all patients enrolled in the protocol at baseline (before treatment) and during each follow-up blood draw. The hypothesis is that patients with suboptimal DRC will do better with chemotherapy than patients with efficient DRC.
* To extract DNA and genotype for polymorphisms in genes involved in the nucleotide excision repair pathway and in those involved in response to pain (opioid receptors, dopamine receptors, COMT). We hypothesize that:

  1. Polymorphisms in NER genes that modulate DNA repair capacity will also effect response to chemotherapy and to outcome.
  2. Cytokine gene polymorphisms account for variations in symptom outcomes (specific symptoms and symptom clusters) before, during and after chemotherapy.
  3. The COMT val/met polymorphism affects the metabolism of catecholamines on the modulation of response to sustained pain.
  4. Dopamine receptor polymorphisms that result in decreased density of dopamine receptors will result in a deficit in the dopamine pathway. that will also affect response to pain.
* To evaluate neurocognitive function to determine the prevalence, severity, and pattern of cognitive symptoms.

One of the ways to learn about the symptoms of chemotherapy is by looking at how certain proteins called cytokines (found in the blood) change during therapy. Another way is to look at how symptoms change during treatment.

Before therapy starts, you will be asked to complete several questionnaires during a visit to the thoracic clinic at M. D. Anderson. These questionnaires measure physical and emotional (mental) symptoms. The questionnaires should take about 60 minutes to finish. You will also be asked to complete some cognitive (mental) questionnaires that take about 25 minutes to complete. During this visit, the research nurse will teach you how to use an interactive voice response telephone system for measuring symptoms. The research nurse will ask you the most convenient time for the telephone calls, and make sure the system is programmed to call you at that time. The date of the call will be at the same or close to the date of your weekly clinic visit.

Symptoms will be monitored weekly during chemotherapy treatment using this interactive voice response telephone system. The automated telephone system will call you once a week, and using the numeric key pad on your telephone, you will rate the severity of your symptoms and how much they interfere in your daily life. Once you complete therapy, the phone system will call every two weeks for up to six months. The information collected by these calls is only being used for this research study.

In addition to the telephone calls, the research nurse will arrange to meet you approximately every 6 weeks at your clinic visit. She will ask you to complete some surveys about your symptoms, mood, and quality of life. This meeting will take about 45 minutes. You will also be asked again to complete some cognitive (mental) questionnaires that take about 25 minutes to complete.

Research staff will also obtain from your medical record clinical information and lab values during your treatment period.

If you have agreed to participate in the companion caregiver study, the study staff will use your demographic and clinical data to study the influence of your symptoms on your caregiver's physical and mental health.

You are encouraged to report your symptoms to your treating physicians during the study, especially if you have any symptom that you rate greater than 7 on the 0 to 10 scale.

This is an investigational study. A total of up to 224 patients will take part in this multicenter study. Up to 112 will be enrolled at M. D. Anderson.

Study participants enrolled at M. D. Anderson will have additional serum drawn for cytokine analysis and DNA repair capacity. This blood will be drawn at the routine blood draws before treatment begins, and at the beginning of each treatment cycle.

Longitudinal Study of Multiple Symptoms in Advanced Lung Cancer

Longitudinal Study of the Prevalence, Severity, and Interference of Multiple Symptoms in Advanced Lung Cancer

IVR telephone system to collect longitudinal data on symptom patterns and severity using patient tumor response evaluation after 2-3 cycles chemotherapy and total weekly IVR assessment period at 18 weeks.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Venetoclax

Cycle 1 (28-days cycle) Stepwise dose escalation of Venetoclax in all patients with a target dose of 800 mg/d QD PO.

Day 1-7: Venetoclax 200 mg/d QD PO Day 8-14: Venetoclax 400 mg/d QD PO Day 15-28: Venetoclax 800 mg/d QD PO

Cycle 2-12:

Day 1: Rituximab 375 mg/m2 IV Day 1-28: Venetoclax 800 mg/d QD PO

Cycle 1-6:

Day 1: Dexamethasone 20 mg PO Day 1: Rituximab 375 mg/m2 IV Day 1-5: Cyclophosphamide 100 mg/m2 BID PO

Venetoclax; Rituximab

Combination of Dexamethasone / Rituximab / Cyclophosphamide

Birgit Schmelzle

Christian Buske, Prof. Dr.

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease.

Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM.

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease.

Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM.

This study is an International phase II explorative, multicenter, open label, and randomized trial.

The study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B for de novo WM patients in need of treatment (phase II). Stratification factors are MYD88 and CXCR4 status (positive vs. negative). A stratified central block randomization will be used. The central randomization service will be used to avoid predictability of the treatment arm.

The primary goal of this study is to explore the efficacy of Venetoclax plus Rituximab versus Dexamethasone/Cyclophosphamide/Rituximab in the treatment of de novo WM patients (Arm A vs. Arm B).

80 patients are planned to be recruited for this study at approcimately 30 sites in Germany, Greece and France.

Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia

response at C4D1; C7D1 (arm A) / 28 days after C6D1 (arm B); C10D1 (arm A) / post treatment staging 1 (arm B) (categories: CR, VGPR, PR, MR, SD, PD, death)

response rates (CR, VGPR, PR, MR, SD, PD, death)

Best response is determined in the time interval from start of treatment up to 24 months (categories: CR, VGPR, PR, MR, SD, PD, death).

Time to first overall response is defined as the time from randomization to first overall response (MR, PR, VGPR or CR) within 24 months from start of treatment.

Time to first major response is defined as the time from randomization to first major response the patient achieves (CR, VGPR, PR) within 24 months from start of treatment.

EFS is defined as the date of randomization to the first event of death from any cause or progression or stop of treatment due to toxicity or add-on of new anti-cancer therapy.

Remission duration will be calculated in patients with overall response (CR, VGPR, PR, MR) from the first date of response to the date of progression, relapse or death from any cause.

PFS will be calculated from the date of randomization to the following events: the date of progression and the date of death if it occurred earlier.

Lymphoma specific survival is defined as the period from randomization to death from lymphoma or lymphoma related cause (e.g. infections, bleeding, amyloid caused organ failure).

Overall survival is defined as the period from randomization to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.

Adverse events according to NCI-CTCAE version 5.0, SAEs, laboratory parameters (hematology, serum chemistry, b2-microglobulin, coagulation, urine analysis, quantitative immunoglobulins, serum free light chain, cold agglutinin test, serum protein electrophoresis, serum immunofixation, Anti-HIV, HBV, HCV), 12-lead ECG (including PR-, QT- and QTc interval), vital signs (heart rate, blood pressure and temperature)

Quality of Life will be assessed by the FACT-Lym questionnaire which is a scoring instrument to measure the management of chronic illness in lymphoma patients. A higher score indicates a better quality of life

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy of First Line DRC +/- Bortezomib for Patients With Waldenström's Macroglobulinemia	NCT01788020	Waldenström's M...	Dexamethasone, ... Dexamethasone, ...	18 Years -	University of Ulm
Longitudinal Study of Multiple Symptoms in Advanced Lung Cancer	NCT00422500	Lung Cancer	Questionnaire Telephone Inter... Blood Samples	18 Years -	M.D. Anderson Cancer Center
Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia	NCT05099471	Waldenstrom Mac...	Venetoclax; Rit... DRC	18 Years -	University of Ulm
Efficacy of First Line DRC +/- Bortezomib for Patients With Waldenström's Macroglobulinemia	NCT01788020	Waldenström's M...	Dexamethasone, ... Dexamethasone, ...	18 Years -	University of Ulm

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Spots Global Cancer Trial Database for drc

Every month we try and update this database with for drc cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for drc cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.