Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Lymphoid

Lymphoma

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Prolymphocytic

Leukemia, Hairy Cell

Chronic Graft Versus Host Disease

Lymphosarcoma

Chronic Lymphocytic Leukemia

Hairy Cell Leukemia

All Drugs and Chemicals

Mitogens

AGS67E

Immunoconjugates

Immunologic Factors

Participants will receive 0.05 milligram per kilogram (mg/kg) AGS67E without growth factor (GF) by intravenous infusion once every three weeks.

Participants will receive 0.1 mg/kg AGS67E without GF by intravenous infusion once every three weeks.

Participants will receive 0.3 mg/kg AGS67E without GF by intravenous infusion once every three weeks.

Participants will receive 0.6 mg/kg AGS67E without GF by intravenous infusion once every three weeks.

Participants will receive 0.9 mg/kg AGS67E without GF by intravenous infusion once every three weeks.

Participants will receive 1.2 mg/kg AGS67E without GF by intravenous infusion once every three weeks.

Participants will receive 1.2 mg/kg AGS67E with GF by intravenous infusion once every three weeks.

Participants will receive 1.5 mg/kg AGS67E with GF by intravenous infusion once every three weeks.

Participants will receive 1.8 mg/kg AGS67E with GF by intravenous infusion once every three weeks.

Associate Medical Director

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of AGS67E both without and with myeloid growth factor (GF) in subjects with refractory or relapsed lymphoid malignancies. Immunogenicity and anticancer activity of AGS67E will also be assessed.

The dose escalation study will have two parts:

1. Dose Escalation of AGS67E without myeloid growth factor (GF)
2. Dose Escalation of AGS67E with myeloid growth factor (GF)

Subjects will be enrolled sequentially into dose cohorts starting with AGS67E without GF.

All subjects will receive a single 30 minute intravenous (IV) infusion of AGS67E once every three weeks. Subjects will continue treatment until disease progression, intolerability of AGS67E, investigator decision or consent withdrawal.

This dose escalation will first determine the maximum tolerated dose (MTD) of AGS67E without GF and then determine the MTD of AGS67E with GF. Once an MTD has been established, the study may enroll subjects into respective expansion cohorts of 12 subjects each at doses recommended by the data review team (DRT) (expansion cohort without GF and/or expansion cohort with GF).

During dose escalation, the Data Review Team will review cumulative unaudited data on an interim basis to review subject safety, recommend exploring additional doses and/or schedules, or the expansion of existing cohorts.

A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies

A Phase 1 Study Evaluating Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Tumor response is defined as either a complete response (CR) or partial response (PR)

ORR for a cohort is defined as the percentage of subjects who experience a best response of either complete response (CR) or partial response (PR) in that cohort.

Astellas Pharma Global Development, Inc.

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Lymphoma, Mantle-Cell

Waldenstrom Macroglobulinemia

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Lymphoma, Non-Hodgkin

Mantle Cell Lymphoma

Antineoplastic Agents

ON 01910

Protein Kinase Inhibitors

Enzyme Inhibitors

ON01910 Na

Mark J Roschewski, M.D.

Background:

* Mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and other lymphoid malignancies are all incurable lymphoid malignancies that mainly affect persons in their late 60s and early 70s. Conventional chemotherapy can achieve high rates of clinical response, but relapse following these responses is almost universal. Patients with lymphoid malignancies relapse because their tumor cells become resistant to chemotherapy; therefore, new types of drugs are needed for better treatment responses.
* The investigational drug ON 01910.Na has been shown to be active against MCL and CLL cells, but further research is needed to determine the most safe and effective dose for this drug.

Objectives:

* To determine the maximum tolerated dose (the highest dose that does not cause unacceptable side effects) of ON 01910.Na in patients with cancers of the lymphoid cells.
* To study the effects that ON 01910.Na has on cancers of the lymphoid cells.

Eligibility:

* Patients 18 years of age and older who have been diagnosed with cancer of the lymphoid cells, and who have not been able to take or have not benefitted from existing treatment options.

Design:

* Evaluations before the treatment period:
* Full medical history and physical examination, and pregnancy test for women.
* Blood and urine tests.
* Disease evaluation with computerized tomography (CT) scan, magnetic resonance imaging (MRI), electrocardiogram; bone marrow and lymph node biopsies; and skeletal x-rays, if clinically indicated.
* Treatment with ON 01910.Na:
* Different research subjects will receive increasing doses of ON 01910.Na to determine which dose is considered safe.
* To reduce the risk of one rare serious side effect of treatment for myeloid malignancies, patients will take allopurinol 12 hours before and 7 days after each drug infusion, one 300 mg pill each day.
* Cycles 1 2: Patients will be admitted to the clinical center for 2 days at the beginning of each cycle. Each cycle involves intravenous infusion of ON 01910.Na continuously for a period of 48 hours, followed by 12 days of observation. Researchers will try to maintain the schedule of 2 days of infusion every 14 days, but the interval between doses may be extended if patients experience delayed recovery blood counts.
* Cycles 3 4: Patients who are doing well and choose to continue may receive an additional two cycles (2 days of inpatient infusion followed by 12 days of outpatient observation). At the end of cycle 4, researchers will determine if the disease is responding to therapy. Patients who experience side effects may continue to take ON 01910.Na at a lower dose or may stop receiving the drug.
* Patients who respond well to four cycles of ON 01910.Na may be eligible for additional cycles of ON 01910.Na.
* Patients who need to start another medication to treat their disease will stop taking ON 01910.Na, and the researchers will perform a final study visit 2 weeks after the last dose of ON 01910.Na. After that, participation in the study will be complete.

Mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and the related lymphoid malignancies included in this protocol are all incurable lymphoid malignancies that mainly affect persons in their late 60s and early 70s. Conventional chemotherapy can be effective at achieving high rates of clinical response, but relapse following these responses is almost universal. Response rates in the relapsed setting are inferior due to acquired resistance of the tumor cells, and new therapies with novel mechanisms of action are needed. Our aim in this study is to specifically address the needs of these patients for whom few effective treatments are available.

Patients with lymphoid malignancies relapse due to acquired resistance of tumor cells to chemotherapy agents and innovative targeted therapies which overcome these mechanisms of resistance are needed. One such investigational drug, ON 01910.Na, is a potent and selective inhibitor of the cell cycle and leads to reduction in cyclin D1 expression. In vitro, ON01910.Na shows activity against CLL and MCL cell lines with resultant cellular death. The overexpression of cyclin D1 in these related lymphoid malignancies provides a rationale for its use in selected patients with these conditions.

We therefore propose this non-randomized, pilot, dose-escalating Phase I study of ON 01910.Na in patients with MCL, CLL, MM and related lymphoid malignancies who have relapsed after or are refractory to standard therapy.

The primary objective is to determine the toxicity profile (including the maximum tolerated dose and recommended phase II dose) of ON 01910.Na when administered the first 2 (or amended later to 3) days of a 2-week cycle in escalating doses in patients with MCL, CLL, MM and related lymphoid malignancies.

The first cohort was dosed at 1200mg/m2/day times 2 days. The second cohort was dosed at 1500mg/m2/day for 2 days. Three subjects were enrolled into the third cohort at 1800mg/m2/day times 2 days. One subject completed the 1800mg/m2/ day times 2 days dosing scheme. Two subjects stopped study drug after the first dose due to progressive disease. The 3 subjects who received 1800mg/m2/day times 2 days will compose cohort 3. New safety data from the drug manufacturer lead to Amendment L, which changed the dosing from 48 hours to 72 hours. On November 18, 2010, the IRB approved Amendment L, which changed the dosing for the new cohorts 4 and 5 to 1800mg/day times 3 days, and 2100mg/day times 3 days, respectively.

Secondary objectives include, the biological effects of ON 01910.Na (for example cyclin D1 expression) on cell-cycle pathways of cells obtained from blood, lymph nodes or bone marrow, the toxicity profile of ON 01910.Na with subsequent dosing after 2 cycles of therapy, early indications of biologic activity after 4 cycles of therapy, evaluation of the pharmacokinetics of ON 01910.Na at the RPTD level, and indications of biologic activity during extended access (after 4 cycles (day 56)).

The primary endpoint will be the toxicity profile at each dose level through day 28 (cycle 2 day 14).

Secondary endpoints include the reduction in lymph nodes, quantification of circulating lymphoma cells, assessment of extranodal disease sites, and/or measurement of the malignant monoclonal proteins in the serum or urine after 4 cycles of therapy (day 56).

A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With Relapsed Mantle Cell Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, and Related Lymphoid Malignancies

A Pilot Study of the Safety and Efficacy of Escalating Doses of ON 01910.Na in Patients With Relapsed Mantle Cell Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, and Related Lymphoid Malignancies

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies	NCT02175433	Relapsed Lympho... Refractory Lymp...	AGS67E	18 Years -	Astellas Pharma Inc
A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies	NCT02175433	Relapsed Lympho... Refractory Lymp...	AGS67E	18 Years -	Astellas Pharma Inc
A Pilot Study of the Safety and Activity of Escalating Doses of ON 01910.Na in Patients With Relapsed Mantle Cell Lymphoma, Multiple Myeloma, Chronic Lymphocytic Leukemia, and Related Lymphoid Malignancies	NCT00861510	Lymphoma, Mantl... Leukemia, Lymph... Leukemia, Hairy... Waldenstrom Mac... Multiple Myelom...	ON01910 Na	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

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