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A Phase 1b Study of GDC-0449 Following Autologous Transplantation in Patients With High Risk First Remission or Relapsed Multiple Myeloma

Phase 1
18 Years
Open (Enrolling)
Smoldering Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

A Phase 1b Study of GDC-0449 Following Autologous Transplantation in Patients With High Risk First Remission or Relapsed Multiple Myeloma


I. To determine if GDC-0449 is able to reduce myeloma cancer stem cells (CSC) when given to
patients with MM following autologous stem cell transplantation.


I. To determine whether GDC-0449 is inhibiting the Hh pathway in patients with MM following
autologous transplantation by measuring downstream targets of Hh using qRT-PCR on plasma
cells and MM CSC obtained from blood and bone marrow of patients undergoing treatment.

II. To determine whether changes in MM CSC as measured by clonogenic assays on bone marrow
are seen in response to GDC-0449 and whether these changes predict recurrence.

III. To determine whether changes in MM CSC can be measured with similar or better accuracy
using peripheral blood flow cytometry as compared to bone marrow clonogenic assays.

IV. To determine the safety and toxicity profile for treatment with GDC-0449 following
autologous transplantation in patients with high risk or relapsed MM.

V. To characterize the pharmacokinetics (PK) of GDC-0449 (total and unbound) at steady-state
and correlate this with pharmacodynamic (PD) endpoints.

VI. To determine the one year progression free survival for patients given GDC-0449
following autologous transplantation.

OUTLINE: This is a multicenter study.

Patients receive Hedgehog antagonist GDC-0449 orally (PO) once daily on days 1-28. Treatment
repeats every 28 days for up to 11 courses in the absence of disease progression or
unacceptable toxicity.

Patients undergo blood and bone marrow sample collection at baseline and periodically during
study for pharmacokinetic and other correlative studies.

After completion of treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed multiple myeloma meeting
criteria with symptomatic disease requiring treatment; patients considered to have
high risk disease (defined as chromosome 13 deletion by cytogenetics. t(4;14),
t(14;16) or 17p deletion by FISH, B2-M > 5.5 g/dL, IgA phenotype) in first remission
(>= PR) or Patients with relapsed myeloma responding to salvage therapy (>= PR) based
on the International Uniform Response Criteria are eligible

- Patients must have measurable disease utilizing serum or urine protein
electrophoresis or serum kappa / lambda light chain assay

- Patients must be planning to proceed to single autologous transplantation according
to institutional standards and must receive this transplantation prior to
implementation of GDC-0449

- Concomitant bisphosphonate use is allowed as clinically indicated

- Life expectancy of greater than 6 months

- ECOG performance status =< 2 (Karnofsky >= 60%)

- The effects of GDC-0449 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because Hh signal pathway inhibitors as well as
other therapeutic agents used in this trial are known to cause interruption of the
embryonic signaling pathway and may lead to serious or life-threatening birth
defects, including brain deformities, facial malformation, heart problems, or
abnormal organs; therefore, women of child-bearing potential and men must use two
forms of contraception (i.e., barrier contraception and one other method of
contraception) at least 4 weeks prior to GDC-0449 treatment, for the duration of
study participation, and for at least 12 months post-treatment; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- HIV-positive patients without a prior AIDS-defining illness and a CD4 count
400/millimeter^3 and either do not require anti-HIV therapy or are taking anti-HIV
therapy that would not interfere with GDC-0449 (e.g. not taking zidovudine, protease
inhibitors or non-nucleoside reverse transcriptase inhibitors) are eligible

Exclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in MM CSC counts

Outcome Description:

Estimated using a simple linear regression model.

Outcome Time Frame:

Baseline up to 6 months

Safety Issue:


Principal Investigator

Carol Huff

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Smoldering Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



University of Maryland Greenebaum Cancer Center Baltimore, Maryland  21201
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital Baltimore, Maryland  21231