RO4929097 After Autologous Stem Cell Transplant in Treating Patients With Multiple Myeloma

This study has been withdrawn prior to enrollment.
(Because of "No Participant Enrollment.")
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01251172
First received: November 30, 2010
Last updated: October 25, 2013
Last verified: October 2013
  Purpose

This phase II clinical trial is studying how well gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) after autologous stem cell transplant works in treating patients with multiple myeloma. Giving chemotherapy, such as melphalan, before autologous stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Before treatment, stem cells are collected from the patient's blood and stored. After chemotherapy, the stem cells are returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving RO4929097 after autologous stem cell transplant may kill more cancer cells.


Condition Intervention Phase
Refractory Multiple Myeloma
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Procedure: hematopoietic stem cell mobilization
Drug: melphalan
Procedure: autologous hematopoietic stem cell transplantation
Procedure: in vitro-treated peripheral blood stem cell transplantation
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of RO4929097 to Eradicate Residual Disease in Patients With Multiple Myeloma Post Single Autologous Stem Cell Transplant

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Overall response rate of gamma-secretase/Notch signalling pathway inhibitor RO4929097 in eradicating residual/persistent disease, defined as conversion from VGPR to CR or sCR [ Time Frame: Up to 42 days ] [ Designated as safety issue: No ]
    A Simon's 2-stage optimal Phase II design will be used to monitor the study.


Secondary Outcome Measures:
  • Clonogenic myeloma progenitor cells [ Time Frame: At baseline, at 100 days post-transplant, and at 6 weeks ] [ Designated as safety issue: No ]
    Logistic regression models will be used to study the association of clinical response (relapse) and the myeloma stem cell kinetics (present and absent of cell, and/or percentage of cells).

  • Incidence of adverse events and abnormal laboratory variables as assessed according to the NCI-CTCAE version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Adverse events will be reported in frequency tables overall, by intensity, and by relationship.


Enrollment: 0
Study Start Date: December 2010
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (RO4929097 after autologous stem cell transplant)

STEM CELL TRANSPLANTATION AND CHEMOTHERAPY: Patients undergo standard mobilization and collection of autologous peripheral stem cells (>= 4.0 x 10^6 CD34+ cells/kg). Patients then receive high-dose melphalan IV on days -3 and -2 and undergo autologous stem cell transfusion on day 0. Patients with progressive disease, stable disease, partial response, stringent complete response, or complete response are taken off study; patients with residual/persistent disease (VGPR) continue to therapeutic treatment.

THERAPEUTIC TREATMENT: Beginning 100-110 days after transplantation, patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Procedure: hematopoietic stem cell mobilization
Undergo standard mobilization
Drug: melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
Procedure: autologous hematopoietic stem cell transplantation
Undergo in vitro treated autologous peripheral blood stem cell transplant
Procedure: in vitro-treated peripheral blood stem cell transplantation
Undergo in vitro treated autologous peripheral blood stem cell transplant
Other Names:
  • in vitro-treated PBPC transplantation
  • in vitro-treated PBSC
  • in vitro-treated peripheral blood progenitor cell transplantation
  • PBPC transplantation, in vitro-treated
  • peripheral blood progenitor cell transplantation, in vitro-treated
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally
Other Names:
  • R4733
  • RO4929097
Other: laboratory biomarker analysis
Correlative studies

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  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a diagnosis of multiple myeloma as defined below with staging based on the International Staging System:

    • Multiple myeloma - all three required (Note: these criteria identify stage 1B and stages II and IIIA/B myeloma by Durie/Salmon stage; stage 1A becomes smoldering or indolent myeloma):

      • Monoclonal plasma cells in the bone marrow ≥ 10% and/or presence of a biopsy-proven plasmacytoma
      • Monoclonal protein present in the serum and/or urine (if no monoclonal protein is detected [non-secretory disease], then >= 30% monoclonal bone marrow plasma cells and/or biopsy-proven plasmacytoma is required)
      • Myeloma-related organ dysfunction (1 or more) (a variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy; such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related):

        • Calcium elevation in the blood (serum calcium > 10.5 mg/L or upper limit of normal)
        • Renal insufficiency (serum creatinine > 2mg/dL)
        • Anemia (hemoglobin < 10 g/dL or 2 g < normal)
        • Lytic bone lesions or osteoporosis (if a solitary [biopsy-proven] plasmacytoma or osteoporosis alone [without fractures] are the sole defining criteria, then > 30% plasma cells are required in the bone marrow)
  • Patients must have measurable disease

    • Patients with non-secretory multiple myeloma will be eligible only if the baseline serum free light chain level is elevated (>= 10 mg/dL)
  • For therapeutic treatment with RO4929097, patients must have peripheral blood stem cell collection of >= 4.0 x 10^6 cells/kg (patient's ideal body weight)
  • ECOG performance status =< 2, Karnofsky >= 60%
  • Estimated life expectancy of at least 12 weeks
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9.0 g/dL
  • NOTE: Patients should not require chronic supportive growth factor administration or transfusions to meet treatment eligibility criteria (e.g., G-CSF for ANC eligibility)
  • Serum creatinine =< 2.0 mg/dL OR a measured creatinine clearance by 24-hour urine collection >= 40 mL/min (a calculated creatinine clearance by Cockcroft-Gault formula is acceptable in lieu of a measured value)
  • Total bilirubin within normal institutional limits
  • AST (SGOT)/ALT SGPT) =< 2.5 X institutional ULN
  • Patients with uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia, defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation, are excluded from this study
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment
  • No requirement for routine use of hematopoietic growth factors (including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or platelet counts above the required thresholds for study entry

    • Use of erythropoietin-stimulating agents and red cell transfusions are also not permitted prior to initiation of RO4929097
  • Patient must meet the institutional standard criteria for undergoing high-dose chemotherapy and autologous stem cell transplant
  • No serious concomitant systemic disorders (including active infections) that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator
  • No uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • A history of torsades de pointes
    • Cardiac arrhythmia other than chronic, stable atrial fibrillation
    • Psychiatric illness/social situations that would limit compliance with study requirements
  • No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
  • Patients with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel are excluded

    • Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded
  • No condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedure affecting absorption, or active peptic ulcer disease) that impairs the ability to swallow and retain RO4929097
  • Patients who have active hepatitis B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • No second primary malignancy except most situ carcinoma (e.g., in situ carcinoma of the of the cervix, adequately treated non-melanomatous carcinoma of the skin) or other malignancy treated at least 3 years previously with no evidence of recurrence
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097or other agents used in the study
  • There are no limitations on type and amount of prior therapy with the following exception: patients who have had a solid organ transplant are ineligible

    • Acute toxicities of high-dose melphalan therapy must have resolved to the NCI-CTCAE version 4.0 grade 1 or less (with the exception of alopecia)
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
  • No concurrent drugs, food, supplements, or over-the-counter medications that may interfere with the metabolism of RO4929097, including ketoconazole and fresh-squeezed grapefruit juice
  • Patients may not be receiving any other investigational agents
  • Patients may not be receiving antiarrhythmics or other medications known to prolong QTc
  • No other investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy
  • No patients who have had any chemotherapy or radiotherapy post-autologous stem cell transplant prior to entering the therapeutic arm of the study or those who have not recovered from the high-dose melphalan and autologous stem cell transplant
  • For therapeutic treatment with RO4929097, the acute toxicities of the high-dose melphalan therapy must have resolved to the NCI-CTCAE version 4.0 Grade 1 or less (with the exception of alopecia)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01251172

Sponsors and Collaborators
Investigators
Principal Investigator: Mecide Gharibo Rutgers Cancer Institute of New Jersey
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01251172     History of Changes
Other Study ID Numbers: NCI-2011-02555, NCI-2011-02555, CDR0000689644, 011003, 8540, U01CA132194
Study First Received: November 30, 2010
Last Updated: October 25, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Melphalan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 30, 2014