Clinical Trials

OBJECTIVES:

     Primary

       -  To compare the overall survival of older patients with newly diagnosed acute myeloid leukemia (AML) treated with clofarabine as induction therapy and consolidation therapy vs standard daunorubicin hydrochloride and cytarabine.

     Secondary

       -  To evaluate complete remission (CR) rates, duration of remission, and toxicity/treatment-related mortality of patients treated with these regimens.

       -  To evaluate the feasibility of consolidation therapy with reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical donors, in terms of the incidence of successful engraftment, acute and chronic graft-vs-host disease, and transplant-related mortality in select patients age 60-69 years who achieve a response to induction therapy.

       -  To determine the impact of reduced-intensity conditioning and allogeneic stem cell transplantation on overall survival of select patients.

       -  To compare the duration of remission and disease-free survival of patients in CR following completion of consolidation therapy who are subsequently randomized to receive decitabine as maintenance therapy vs observation.

       -  To perform expression and methylation profiling in patients treated with decitabine as maintenance therapy and to correlate their integrated epigenetic signatures with response to decitabine.

       -  To examine the epigenetic profiles of remission marrow in patients randomized to receive decitabine as maintenance therapy vs observation to determine whether epigenetic signatures of apparently morphologically normal bone marrow is predictive of relapse or response to decitabine.

       -  To explore the possible association of response to clofarabine with nucleoside transporters hENT1, hCNT3, and ABC-transporter P-glycoprotein.

       -  To assess the intensity of expression of CXCR4 on diagnostic leukemia cells and to correlate this parameter with other established prognostic factors.

       -  To assess the entire spectrum of somatic mutations and affected pathways at diagnosis of AML and elucidate the association between gene mutation and outcome.

     Tertiary

       -  To compare health-related quality of life (QOL) (physical, functional, leukemia-specific well-being) and fatigue in patients treated with clofarabine vs standard induction therapy.

       -  To measure the change in health-related QOL that occurs over time.

       -  To comprehensively assess patient function at the time of study enrollment.

       -  To determine if components of a comprehensive geriatric assessment or QOL scale predict ability to complete treatment for AML.

       -  To describe the impact of transplantation on QOL in patients with AML over 60 years of age.

     OUTLINE: This is a multicenter study. Patients are stratified according to age (60-69 years vs ≥ 70 years), , disease type (secondary vs de novo), therapy-related AML (yes vs no), and antecedent hematologic disorder (yes vs no).

       -  Induction therapy: Patients are randomized to 1 of 2 treatment arms.

            -  Arm I (standard therapy): Patients receive daunorubicin hydrochloride IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 14.

            -  Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 21 and no later than day 56.

     Patients who achieve a complete remission (CR) or CR incomplete (CRi) after induction therapy proceed to consolidation therapy. Patients who are 60-69 years of age who achieve a "morphologic leukemia-free state" after induction therapy and who have an HLA-identical donor proceed to allogeneic stem cell transplantation. Patients undergoing second induction who do not achieve CR by day 56 of the start of re-induction are taken off protocol.

       -  Consolidation therapy: Beginning within 60 days after documentation of CR or CRi, patients receive consolidation therapy in the same arm they were randomized to for induction therapy.

            -  Arm I (standard therapy): Patients receive cytarabine IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

            -  Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4-6 weeks for 2 courses.

     Patients who remain in CR after completion of consolidation therapy proceed to maintenance therapy.

       -  Maintenance therapy: Beginning within 60 days after completion of consolidation therapy, patients receive maintenance therapy and are randomized to 1 of 2 arms.

            -  Arm I: Patients undergo observation monthly for 12 months.

            -  Arm II: Patients receive decitabine IV over 1 hour on days 1-3. Treatment repeats every 4 weeks for 12 months the absence of unacceptable toxicity.

       -  Allogeneic stem cell transplantation with reduced-intensity conditioning regimen: Patients begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.

            -  Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and anti-thymocyte globulin IV over 4-6 hours on days -4 to -2.

            -  Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

     Patients complete quality-of-life questionnaires periodically, including health-related quality of life, physical and functional well-being, and fatigue questionnaires.

     Peripheral blood, bone marrow, and karyotype samples are collected periodically for cytogenetic analysis and other correlative laboratory studies.

     After completion of study treatment, patients are followed up periodically for ≥ 5 years.

Depression is common in patients with advanced cancer.  Current antidepressants, while effective, have an onset of action of at least several weeks.  Ketamine has emerged as a drug with promise for cancer patients.  It has been shown to potentiate opiate analgesic effects.  Single dose parenteral and enteral administration studies in medically healthy treatment-resistant depressed patients have shown rapid relief of symptoms.  A recent two patient case series reported a rapid and moderately sustained symptom reduction in depression and anxiety in palliative care patients following a single dose of oral ketamine 0.5 mg/kg, with no adverse effects.  Benefit was seen as little as 1 hour after the administration and sustained up to 30 days.  These case reports generate hypotheses of efficacy for ketamine in the treatment of depression and anxiety in patients with advanced cancer.  This study is a randomized, double-blind, placebo-controlled investigation of these hypotheses.

OBJECTIVES: Primary - To determine whether administering high-dose thoracic radiotherapy, 70 Gy (2 Gy once daily over 7 weeks) or 61.2 Gy (1.8 Gy once daily for 16 days followed by 1.8 Gy twice daily for 9 days), will improve median and 2-year survival compared with 45 Gy (1.5 Gy twice daily over 3 weeks) in patients with limited-stage small cell lung cancer. Secondary - To compare treatment-related toxic effects of thoracic radiotherapy regimens in patients with limited-stage small cell lung cancer. - To compare response rates, failure-free survival, and toxicity of thoracic radiotherapy regimens in patients with limited-stage small cell lung cancer. - To compare rates of local relapse, distant metastases, and brain metastases with these regimens. - To describe the patterns of use of thoracic intensity-modulated radiotherapy (IMRT) in patients with limited-stage small cell lung cancer. OUTLINE: This is a 2-part, multicenter, randomized study. Patients are stratified according to gender, weight loss 6 months prior to study entry (≤ 5% of body weight vs > 5% of body weight), ECOG performance status (0 vs 1 vs 2), radiotherapy technique (intensity-modulated radiotherapy vs 3-dimensional conformal radiotherapy), and radiotherapy start time (at first course of protocol chemotherapy, after one course of prior non-protocol chemotherapy vs at first course of protocol chemotherapy, without prior non-protocol chemotherapy vs at second course of protocol chemotherapy, without prior non-protocol chemotherapy). - Part 1: Patients are randomized to 1 of 3 treatment arms. - Arm I: Patients undergo standard-dose (45 Gy given in 30 treatments) thoracic radiotherapy twice daily, 5 days a week, for 3 weeks. Patients also receive cisplatin IV on day 1 and etoposide IV on days 1, 2, and 3. - Arm II: Patients undergo higher-dose (70 Gy given in 35 treatments) thoracic radiotherapy once daily, 5 days a week, for 7 weeks. Patients also receive cisplatin and etoposide as in arm I. - Arm III: (discontinued as of 03/10/13) Patients undergo higher-dose (61.2 Gy given in 34 treatments) thoracic radiotherapy once daily, 5 days a week, during the initial 16 days (approximately 3 weeks) of treatment and then twice daily, 5 days a week, for the final 9 days (approximately 2 weeks) of treatment. Patients also receive cisplatin and etoposide as in arm I. In all arms, treatment with cisplatin and etoposide repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. - Part 2: An interim analysis was conducted after accrual of 30 patients per arm and one experimental arm based upon a comparison of treatment-related toxicity was selected. The most toxic experimental arm was discontinued, and the trial continues comparing standard therapy (arm I) to the selected experimental regimen (arm II) as described in part 1. Prophylactic radiotherapy: Within 3-6 weeks after completion of chemotherapy, patients with responding disease are eligible to undergo prophylactic radiotherapy to the brain once a day, 5 days a week, for 2 weeks. After completion of study treatment, patients are followed up at least every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years or until disease progression. At disease progression, patients are followed up every 6 months.

OBJECTIVES: Primary - Determine the impact of the intervention program (IP) on adherence to mercaptopurine (6MP) using the following adherence assessments: Frequency of 6MP dosing using MEMS (primary measure of adherence); 6MP dosage- and thiopurine methyltransferase (TPMT)-normalized serial red blood cell (RBC) thioguanine nucleotide (6TGN) levels; and self-report of adherence. Secondary - Examine the modifying effect of socio-demographic and clinical characteristics as well as health beliefs/knowledge on changes in adherence with the IP. OUTLINE: This is a multicenter study. Patients are stratified according to ethnic background (Hispanic vs non-Hispanic white vs African-American). Patients are randomized to 1 of 2 intervention arms. - Arm I: Patients receive the Patients Supply Kit containing an electronic pill monitoring system, a Medication Event Monitoring Systems (MEMS®) medication bottle with TrackCap™ with standard resistant cap, and written instructions for the patient and pharmacist. Parents and/or caregivers are also trained to supervise patients' intake of the medication. Beginning on day 1, patients start using the MEMS® medication bottle with TrackCap™ . Clinical research assistants contact patients and parents by telephone the next day to confirm that TrackCap™ is being used, to identify any obstacles, and to determine solutions. Beginning on day 29, patients and caregivers view an interactive multimedia educational program on-line or via DVD. Patients also receive a customized electronic mercaptopurine schedule and automated customized text message reminders delivered via cellular phone or web-based interface. Patients and caregivers are instructed to return the MEMS® medication bottle with TrackCap™ to the clinic by day 141. - Arm II: Patients receive the usual standard of care and the mercaptopurine from the MEMS® medication bottle with TrackCap™ as patients in arm I. Patients and parents and/or caregivers in both arms complete the Demographic and the Acculturation Questionnaires on day 1. Patients and/or caregivers in arm I also complete the Adherence Questionnaires on days 29, 57, and 141 and the Intervention Rating Questionnaire on day 141. Blood samples are collected on days 1, 29, 57, and 141 for thiopurine methyltransferase phenotyping and thioguanine nucleotide levels by high-performance chromatography.

This study will be a Phase I, open-label, non-randomized, dose-finding trial conducted at multiple clinical centers. The study is designed to determine the safety, tolerability and PK of TKM-080301 in adult patients with solid tumors or lymphomas that are refractory to standard therapy or for whom there is no standard therapy.

OBJECTIVES:

     Primary

       -  To determine the maximum tolerated dose of lenalidomide when given in combination with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with newly diagnosed stage II-IV diffuse large cell or grade 3 follicular B-cell lymphoma. (Phase I)

       -  To assess the efficacy of this regimen, in terms of event-free survival and response rate, in these patients. (Phase II)

       -  To assess the safety of this regimen in these patients. (Phase II)

     Secondary

       -  To assess the host immune function at baseline and after treatment and correlate these parameters with tumor response and event-free survival.

     OUTLINE: This is a multicenter, phase I dose-escalation study of lenalidomide followed by a phase II study.

       -  Phase I: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, oral prednisone on days 1-5, and oral lenalidomide on days 1-10. Patients also receive pegfilgrastim subcutaneously on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

       -  Phase II: Patients receive lenalidomide at the maximum tolerated dose determined in phase I and rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone, and pegfilgrastim as in phase I.

     Blood is collected at baseline, before course 3, and after completion of study treatment for translational research studies. Research studies include immune function and cytokine analysis, T- and B- quantitative lymphocyte analysis, and single nucleotide polymorphism analysis.

     After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

This is a multicenter, randomized, Phase 3 study comparing two drug regimens (arms) as the front-line treatment of elderly patients aged 70 years or older with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy.  In Arm A, sapacitabine is administered in alternating cycles with decitabine, and in Arm C decitabine is administered alone. The primary efficacy endpoint is overall survival. The study is designed to demonstrate an improvement in overall survival of Arm A versus Arm C.

PRIMARY OBJECTIVES:  I. To determine the progression-free survival of erlotinib (erlotinib) and bevacizumab versus that of erlotinib alone for the purpose of deciding if the combination arm is worth pursuing in a phase III trial.  SECONDARY OBJECTIVES:  I. To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone. II. To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone. III. To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R EGFR point mutations. IV. To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. TERTIARY OBJECTIVES:  I. To correlate EGFR mutations detected in plasma deoxyribonucleic acid (DNA) with those detected in tumor DNA. II. To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods. III. To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). IV. To prospectively evaluate the predictive value of plasma vascular endothelial growth factor A (VEGF-A) levels on progression free survival in patients treated with erlotinib alone or in combination with bevacizumab.  OUTLINE: Patients are randomized to 1 of 2 treatment arms.   ARM A: Patients receive erlotinib orally (PO) once daily (QD) on days 1-21.  ARM B: Patients receive erlotinib as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1.   In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.  After completion of study treatment, patients are followed up periodically for up to 5 years.

PRIMARY OBJECTIVES: I. Evaluate the overall and event-free survival of younger patients with newly diagnosed stage I favorable histology Wilms' tumor (< 2 years of age and < 550gms) treated with nephrectomy only (very low risk), or with newly diagnosed stage III favorable histology Wilms tumor with possible nephrectomy followed by vincristine, dactinomycin, doxorubicin hydrochloride, and radiotherapy (standard risk). SECONDARY OBJECTIVES: I. Determine the effects of adding doxorubicin hydrochloride to the regimen for patients with stage I or II favorable histology found to have a high-risk biological marker. II. Determine whether the omission of adjuvant therapy increases the incidence of contralateral kidney lesions in patients with very low-risk disease treated by nephrectomy and observation only. III. Determine whether the omission of adjuvant therapy increases the incidence of renal failure in patients with very low-risk disease who have metachronous relapse. IV. Correlate study outcomes in patients with standard-risk disease with biological data from tissue collections on protocol study COG-AREN03B2. OUTLINE: This is a multicenter study. Patients are stratified according to clinical and biological risk factors (very low risk vs standard risk). STRATUM I: (very low-risk disease) Patients undergo nephrectomy only. If they meet criteria, they are then observed periodically for 5 years. Patients with recurrent disease undergo surgery (immediate or delayed) and receive chemotherapy as in stratum III. Patients with no metachronous renal disease receive radiotherapy. Patients with metachronous disease undergo renal-sparing surgery and chemotherapy as in stratum III, but no radiotherapy. Treatment continues for up to 25 weeks. STRATUM II: (standard-risk, stage I or II disease with adverse biological marker) Patients undergo nephrectomy. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1, every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 doses of doxorubicin. Treatment continues for up to 25 weeks. STRATUM III: (standard-risk, stage III disease) Patients undergo nephrectomy, if feasible, or biopsy. For patients who undergo biopsy only, definitive surgery is undertaken at week 7 or 13. Between 9 and 14 days post-nephrectomy, patients receive vincristine IV beginning on day 1 every week for 10 weeks then every 3 weeks for a total of 15 doses. Patients receive dactinomycin IV beginning day 1, alternating every 3 weeks with doxorubicin hydrochloride IV for a total of 5 doses of dactinomycin and 4 dose of doxorubicin hydrochloride. Patients undergo radiotherapy over 5-7 days after nephrectomy. Treatment continues for up to 25 weeks. After completion of study treatment, patients are followed periodically for up to 8 years.

OBJECTIVES:

     Primary

       -  Determine the maximum-tolerated dose of dasatinib in combination with bevacizumab in patients with recurrent or progressive high-grade glioma or glioblastoma multiforme. (Phase I*)

       -  Assess the safety and adverse events of this regimen in these patients. (Phase I*)

       -  Estimate and compare the efficacy of these regimens in these patients as measured by progression-free survival at six months. (Phase II)

     Secondary

       -  Describe any preliminary evidence of antitumor activity. (Phase I*)

       -  Describe the overall toxicity associated with this regimen in these patients. (Phase I*)

       -  Estimate and compare the efficacy of these regimens in these patients as measured by overall survival (Phase II)

       -  Assess the impact of these regimens on the patient's quality of life using FACT-Br (no longer assessed as of 5/18/2009) (newly added as of 2/2/2010). (Phase II)

       -  Assess the time to disease progression. (Phase II)

       -  Assess the safety and toxicity of these regimens in this patient population. (Phase II)

       -  Determine the relationship between tumor biomarkers and clinical outcome of patients treated with these regimens. (Phase II) (exploratory)

       -  Assess the utility of dynamic contrast-enhanced MRI as a predictor of response to these regimens. (Phase II) (exploratory)

       -  To assess the utility of MRI diffusion-weighted images (DWI), and specifically the apparent diffusion coefficient (ADC), as a predictor of response and survival in patients treated with bevacizumab/dasatinib combination treatment. (Phase II) (exploratory)

       -  Bank leftover tissue for future NCCTG studies. (Phase II) (exploratory) NOTE: *Phase I completed.

     OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2).

     Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed)

     Phase II (patients are randomized to 1 of 2 treatment arms):

       -  Arm I: Patients receive bevacizumab as in phase I and dasatinib at the MTD as determined in phase I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

       -  Arm II: Patients receive bevacizumab as in phase I and oral placebo once or twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

     Quality of life is assessed by FACT-Br questionnaire at baseline and prior to every other course (no longer assessed as of 5/18/2009)(newly added as of 2/2/2010). Tissue samples are collected at baseline for biomarker studies and assessed by IHC, RT-PCR, and FISH. Patients undergo dynamic contrast-enhanced MRI at baseline, day 3 of course 1, and day 1 of course 2.

     After completion of study therapy, patients are followed up periodically for up to 3 years.