Archive for September 2nd, 2010

Primed Peripheral Blood Stem Cell Autologous Transplantation for Lymphoma and Hodgkin’s Disease

Primed Peripheral Blood Stem Cell Autologous Transplantation for Lymphoma and Hodgkin’s Disease

Filgrastim and Chemotherapy Followed by Peripheral Stem Cell Transplant in Treating Patients With Hodgkin’s Lymphoma or Non-Hodgkin’s Lymphoma
This study has been completed.
First Received: July 5, 2000   Last Updated: July 28, 2009   History of Changes
Sponsor: Masonic Cancer Center, University of Minnesota
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00005985

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplant may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person’s immune system recover from the side effects of chemotherapy.

PURPOSE: This phase II trial is studying how well giving filgrastim together with chemotherapy and peripheral stem cell transplant works in treating patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

Condition Intervention Phase
Lymphoma Biological: filgrastim
Drug: carmustine
Drug: cyclophosphamide
Drug: cytarabine
Drug: dexamethasone
Drug: etoposide
Drug: mitoxantrone hydrochloride
Procedure: peripheral blood stem cell transplantation
Radiation: radiation therapy
Phase II
Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: Primed Peripheral Blood Stem Cell Autologous Transplantation for Lymphoma and Hodgkin’s Disease

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

  • Disease-free survival at 2 years [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • Relapse or progression transplant related mortality at 1½ years [ Designated as safety issue: No ]
Estimated Enrollment: 200
Study Start Date: August 2000
Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

  • Assess the clinical outcomes, survival, and morbidity of transplantation in patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma when treated with filgrastim (G-CSF) followed by high dose chemotherapy plus G-CSF followed by autologous peripheral blood stem cell (PBSC) transplantation.
  • Determine whether sufficient PBSC can be collected for use in autologous transplantation in these patients when mobilized with hematopoietic growth factor alone compared to chemotherapy plus growth factor.
  • Determine whether these primed PBSC support prompt lymphoid and myeloid hematopoietic recovery after transplantation in these patients.
  • Compare the numbers of committed progenitor cells and/or primitive, pluripotential hematopoietic stem cells with these two priming techniques.
  • Compare the numbers of tumor cells in cryopreserved PBSC following these priming techniques.
  • Evaluate response and extended relapse free survival in conjunction with rapid hematopoietic reconstitution and limited transplant associated morbidity and mortality in these patients when treated with these regimens.

OUTLINE: In the first priming phase, patients receive filgrastim (G-CSF) subcutaneously (SQ) daily on days 1-7 and peripheral blood stem cells are collected on days 6-8.

At least 48 hours after the last dose of G-CSF and after the third leukapheresis, patients receive the second priming, which consists of cyclophosphamide IV over 2 hours on day 1 and cytarabine IV over 1 hour every 12 hours for a total of 2 doses on day 1. Patients also receive mitoxantrone IV over 1 hour daily and dexamethasone IV every 12 hours for a total of 4 doses on days 1-2. Patients receive G-CSF SQ daily beginning on day 4 and continuing until the completion of leukapheresis. PBSC are collected on 3 consecutive days after blood counts recover.

In the transplant phase, patients with non-Hodgkin’s lymphoma who have not exceeded pretransplant radiotherapy limits receive cyclophosphamide IV over 2 hours on days -7 and -6 and total body irradiation twice daily on days -4 through -1. Autologous PBSC are reinfused on day 0. Patients receive G-CSF IV daily beginning on day 0 and continuing until day 21 or until blood counts recover.

Patients with Hodgkin’s lymphoma or patients with non-Hodgkin’s lymphoma who have exceeded pretransplant radiotherapy limits receive cyclophosphamide IV over 2 hours daily on days -6 through -3, carmustine IV over 1 hour on day -6, and etoposide IV over 4 hours every 12 hours for a total of 6 doses on days -6 through -4. Autologous PBSC are reinfused on day 0. Patients also receive G-CSF IV daily beginning on day 0 and continuing until day 21 or until blood counts recover.

All patients receive radiotherapy for any residual nodal masses measuring at least 2 cm 5 days a week beginning on day 28.

Patients are followed at day 100, then every 3 months for 1 year, then every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 200 patients will be accrued for this study.

Eligibility

Ages Eligible for Study: up to 70 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria

DISEASE CHARACTERISTICS:

  • One of the following histologically confirmed diagnoses
    • High grade non-Hodgkin’s lymphoma:
      • Immunoblastic or small noncleaved cell lymphoma (Burkitt’s or non-Burkitt’s) in complete or partial remission after initial therapy
      • Localized (stage I or Zeigler stage A) small noncleaved (Burkitt’s or non-Burkitt’s) after relapse or incomplete response to initial therapy
      • Lymphoblastic lymphoma in second or greater complete or partial response
      • High risk lymphoblastic lymphoma in first complete remission or after initial therapy (high risk factors include stage IV disease, LDH greater than 2 times normal, and 2 or more extranodal sites)
    • Intermediate grade non-Hodgkin’s lymphoma:
      • Diffuse large cell lymphoma
      • Diffuse mixed cell lymphoma
      • Diffuse small cleaved cell lymphoma
      • Follicular large cell lymphoma
      • In second or greater complete or partial remission OR
      • High risk in first complete remission or after initial therapy
        • High risk features include:
          • No complete response after 12 weeks of initial combination chemotherapy
          • Bulky disease (greater than 10 cm nodal masses or mediastinal disease involving greater than 1/3 of the chest diameter
          • Malignant pleural effusion
          • Liver involvement
          • LDH greater than 2 times upper limit of normal at diagnosis
          • At least 2 extranodal sites
    • Low grade non-Hodgkin’s lymphoma:
      • Follicular small cleaved cell lymphoma
      • Follicular mixed cell lymphoma
      • Diffuse small lymphocytic lymphoma
      • In first or greater complete response OR
      • Following initial treatment if complete response is not achieved
      • In second or greater complete or partial response if treated at diagnosis without clinical symptoms necessitating treatment
    • T-cell lymphoma (nonlymphoblastic, intermediate, or high grade lymphomas) after initial therapy whether or not complete response is achieved
    • Hodgkin’s lymphoma
      • Stage I and II disease treated with primary radiotherapy and failure of at least one combination chemotherapy regimen
      • Stage III and IV disease with failure on mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)-like regimen, alternative noncross resistant regimen (e.g., doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]), or a combination (e.g., MOPP-ABV)
      • High risk features allowed including:
        • Failure to achieve initial complete remission with MOPP and/or ABVD and crossover or hybrid therapy
        • Relapse within 6 months after initial therapy
        • Relapse after initial radiotherapy with complete response longer than 1 year since initial therapy and subsequent failure on MOPP and/or ABVD or hybrid
      • Bulky mediastinal disease after initial therapy and residual mass of at least 5 cm with other features of persisting disease (e.g., Gallium scan positive, high LDH, enlarging on serial x-rays, or positive biopsy)
  • No HIV or HTLV-1 associated lymphomas
  • No resistant or refractory lymphoma (no partial response following up to 3 courses of combination chemotherapy)
  • No active ischemic or degenerative CNS disease NOTE: A new classification scheme for adult non-Hodgkin’s lymphoma has been adopted by PDQ. The terminology of “indolent” or “aggressive” lymphoma will replace the former terminology of “low”, “intermediate”, or “high” grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age:

  • 70 and under

Performance status:

  • Age 65-70 years:
    • Karnofsky 80-100%
  • Under 65 years:
    • ECOG 0-1 (2 allowed if symptoms are directly related to lymphoma)

Life expectancy:

  • Greater than 8 weeks

Hematopoietic:

  • Not specified

Hepatic:

  • No prior or current chronic liver disease
  • Bilirubin no greater than 1.5 mg/dL
  • AST and alkaline phosphatase less than 2 times normal

Renal:

  • Age 65-70 years:
    • Creatinine clearance greater than 60 mL/min (if creatinine at least 1.5 mg/dL)
  • Under 65 years:
    • Creatinine no greater than 1.5 mg/dL OR
    • Creatinine clearance greater than 50 mL/min

Cardiovascular:

  • LVEF at least 45% by MUGA
  • No symptoms of cardiac disease
  • No active ischemic heart disease
  • No uncontrolled hypertension

Pulmonary:

  • Age 65-70 years:
    • If history of smoking or respiratory symptoms, spirometry and DLCO must be greater than 50% of predicted
  • All ages:
    • No obstructive airway disease
    • No resting hypoxemia (PO_2 less than 80)
    • DLCO at least 50% of predicted

Other:

  • No poorly controlled diabetes

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • See Disease Characteristics
  • Must have prior chemotherapy to attempt to achieve complete response

Endocrine therapy:

  • Not specified

Radiotherapy:

  • See Disease Characteristics
  • No radiotherapy to residual disease prior to transplantation

Surgery:

  • Not specified

Other:

  • Concurrent IV antibiotic therapy allowed for fever or signs of infection

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00005985

Locations
United States, Minnesota
University of Minnesota Cancer Center
Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota

Investigators
Study Chair: Daniel J. Weisdorf, MD Masonic Cancer Center, University of Minnesota

More Information
Additional Information:

No publications provided

ClinicalTrials.gov Identifier: NCT00005985 History of Changes
Other Study ID Numbers: CDR0000067973, UMN-MT-9527, UMN-MT-1995-27
Study First Received: July 5, 2000
Last Updated: July 28, 2009
Health Authority: United States: Federal Government


Keywords provided by National Cancer Institute (NCI):

stage I adult Hodgkin lymphoma
stage II adult Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
recurrent adult Hodgkin lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage I adult diffuse large cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage I adult lymphoblastic lymphoma
stage I adult Burkitt lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III adult Burkitt lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult Burkitt lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult Burkitt lymphoma
stage I adult T-cell leukemia/lymphoma


Additional relevant MeSH terms:

Lymphoma, Large-Cell, Immunoblastic
Hodgkin Disease
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carmustine
Cyclophosphamide
Cytarabine
Dexamethasone
Etoposide
Mitoxantrone
Lenograstim
Dexamethasone acetate
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on August 31, 2010

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MSD Receives European Approval of its Atypical Antipsychotic Medication SYCREST® (asenapine) for the Treatment of Manic Episodes in Bipolar I Disorder


WHITEHOUSE STATION, N.J.–(BUSINESS WIRE)–MSD (MSD is a tradename of Merck & Co., Inc., with headquarters in Whitehouse Station, N.J., U.S.A). announced today that the European Commission has approved the Marketing Authorization Application (MAA) for SYCREST® (asenapine) sublingual tablets for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Today’s decision was based on recommendations from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). The Commission Decision applies to all 27 European Member States.

“Today’s approval provides a new treatment for patients in Europe that is intended to help address the needs of one of the most serious mental illnesses.”

“Bipolar I disorder is difficult to manage, and patients frequently discontinue therapy for a variety of reasons,” said Eduard Vieta, M.D., Ph.D., professor of psychiatry at the University of Barcelona, and director of the Bipolar Disorders Program of the Hospital Clinic, Barcelona, Spain. “Having multiple treatment options is vital for patients, and asenapine represents a new option for this serious disease.”

The European Commission approval of SYCREST, an atypical antipsychotic, for the treatment of manic episodes in bipolar I disorder, was based on a review of efficacy data from a clinical trial program, which included nearly 1,300 patients with bipolar mania. SYCREST is marketed as SAPHRIS® (asenapine) sublingual tablets in the United States.

Clinical Trial Overview

Efficacy of SYCREST was demonstrated in two similarly-designed, three-week, randomized, double-blind, placebo- and active-controlled (olanzapine) monotherapy trials of adult patients who had bipolar I disorder with an acute manic or mixed episode with or without psychotic features. Asenapine demonstrated superior efficacy to placebo in the reduction of manic symptoms over three weeks. A statistically significant difference between asenapine and placebo was seen as early as day two.

These pivotal short-term studies were extended via a nine-week, double-blind, non-inferiority study to assess maintenance of efficacy and safety for up to 12 weeks. Maintenance of effect during the episode after 12 weeks of randomized treatment was observed. These studies were further extended for 40 weeks to assess safety for up to a total 52 weeks.

Additionally, efficacy of SYCREST as adjunctive therapy to the mood stabilizers lithium or valproate was demonstrated in a 12-week, placebo-controlled trial involving 326 patients with a manic or mixed episode of bipolar I disorder, with or without psychotic features. The addition of asenapine as adjunctive therapy in patients who were partially non-responsive to lithium or valproate monotherapy for two weeks at therapeutic serum levels resulted in superior reduction of manic symptoms versus lithium or valproate alone at weeks three and 12.

“SYCREST reflects MSD’s ongoing commitment to innovative therapies in the area of neuroscience,” said Armin Szegedi, M.D., head of Psychiatry, Neuroscience Clinical Research, Merck. “Today’s approval provides a new treatment for patients in Europe that is intended to help address the needs of one of the most serious mental illnesses.”

Approximately 4,500 subjects, including more than 3,150 patients in phase II/III studies, have contributed to asenapine’s safety and tolerability data. In clinical studies, asenapine was generally well tolerated. The most common side effects seen in more than 10% of patients included somnolence and anxiety. Other common side effects seen in between one and 10 patients per 100 included weight gain, increased appetite, dystonia (slow or sustained muscle contractions), akathisia (restlessness), dyskinesia (involuntary muscle contractions), parkinsonism (slow movements, tremor), sedation, dizziness, dysgeusia (change in taste), oral hypoaesthesia (numb feeling of the tongue or in the mouth), increase in alanine aminotransferase (liver protein levels), muscle rigidity, and fatigue. SYCREST is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

In the combined short-term and long-term SYCREST trials, the mean change in body weight for asenapine was 0.8 kg. The proportion of subjects with clinically significant weight gain (≥ 7 % weight gain from baseline at endpoint) in the short-term bipolar mania trials was 6.5% for asenapine compared to 0.6% for placebo.

About Bipolar I Disorder

Bipolar I disorder (also known as manic depression) is a chronic, episodic illness characterized by mania (episodes of elevated moods, extreme irritability, decreased sleep and increased energy), depression (overwhelming feelings of sadness, suicidal thoughts), or a combination of both.

Important Safety Information

Elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic substances are at an increased risk of death. Sycrest is not approved for the treatment of patients with dementia-related psychosis and is not recommended for use in this particular group of patients.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including asenapine. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS Sycrest must be discontinued.

Seizures

In clinical trials, cases of seizure were occasionally reported during treatment with asenapine. Therefore, Sycrest should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.

Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder and close supervision of high-risk patients should accompany treatment.

Orthostatic hypotension

Asenapine may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α1-adrenergic antagonist properties. Elderly patients are particularly at risk for experiencing orthostatic hypotension. In clinical trials, cases of syncope were occasionally reported during treatment with Sycrest. Sycrest should be used with caution in elderly patients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia).

Tardive dyskinesia

Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. In clinical trials, cases of tardive dyskinesia were occasionally reported during treatment with asenapine. The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on Sycrest, discontinuation of treatment should be considered.

Hyperprolactinaemia

Increases in prolactin levels were observed in some patients with Sycrest. In clinical trials, there were few adverse reactions related to abnormal prolactin levels reported.

QT interval

Clinically relevant QT prolongation does not appear to be associated with asenapine. Caution should be exercised when Sycrest is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.

Hyperglycaemia and diabetes mellitus

Hyperglycaemia or exacerbation of pre-existing diabetes has occasionally been reported during treatment with asenapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia or bipolar disorder and the increasing incidence of diabetes mellitus in the general population. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic treatment. Cases of dysphagia were occasionally reported in patients treated with Sycrest.

Body temperature regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic medicines. From the clinical trials, it is concluded that clinically relevant body temperature dysregulation does not appear to be associated with asenapine. Appropriate care is advised when prescribing Sycrest for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity or being subject to dehydration.

Patients with severe hepatic impairment

Asenapine exposure is increased 7-fold in patients with severe hepatic impairment (Child-Pugh C). Therefore, Sycrest is not recommended in such patients.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotic medicinal products, including Sycrest, to patients with Parkinson’s disease or dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Drug Interactions

Caution should be used when asenapine is taken in combination with other centrally acting medicinal products. Patients should be advised to avoid alcohol while taking SYCREST. Additionally, SYCREST should be co-adminsitered cautiously with fluvoxamine (a CYP1A2 inhibitor) and with medicinal products that are both substrates and inhibitors of CYP2D6 (e.g., paroxetine).

For full prescribing information, please refer to the Summary of Product Characteristics.

About MSD

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

SYCREST® is a registered trademark of N.V. Organon, a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A

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