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A Phase 1B/II Study of GDC-0449 (NSC 747691) in Combination With RO4929097, a Gamma-Secretase Inhibitor (GSI) in Advanced/Metastatic Sarcomas

Phase 1/Phase 2
18 Years
Open (Enrolling)
Adult Alveolar Soft-part Sarcoma, Adult Angiosarcoma, Adult Desmoplastic Small Round Cell Tumor, Adult Epithelioid Hemangioendothelioma, Adult Epithelioid Sarcoma, Adult Extraskeletal Chondrosarcoma, Adult Extraskeletal Osteosarcoma, Adult Fibrosarcoma, Adult Leiomyosarcoma, Adult Liposarcoma, Adult Malignant Fibrous Histiocytoma, Adult Malignant Mesenchymoma, Adult Neurofibrosarcoma, Adult Rhabdomyosarcoma, Adult Synovial Sarcoma, Chondrosarcoma, Clear Cell Sarcoma of the Kidney, Conjunctival Kaposi Sarcoma, Dermatofibrosarcoma Protuberans, Gastrointestinal Stromal Tumor, Metastatic Adult Malignant Fibrous Histiocytoma of Bone, Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Metastatic Osteosarcoma, Ovarian Sarcoma, Recurrent Adult Malignant Fibrous Histiocytoma of Bone, Recurrent Adult Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Kaposi Sarcoma, Recurrent Osteosarcoma, Recurrent Uterine Sarcoma, Small Intestine Leiomyosarcoma, Stage III Adult Soft Tissue Sarcoma, Stage III Uterine Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Stage IV Uterine Sarcoma

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Trial Information

A Phase 1B/II Study of GDC-0449 (NSC 747691) in Combination With RO4929097, a Gamma-Secretase Inhibitor (GSI) in Advanced/Metastatic Sarcomas


I. To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097
(RO4929097) when given in combination with fixed-dose Hedgehog antagonist GDC-0449
(GDC-0449) which will become the recommended dose for the phase II portion of this study.
(Phase Ib) II. To assess the progression-free survival (PFS) of the combination of RO4929097
with and without GDC-0449 in two arms of patients with advanced sarcoma. (Phase II)


I. To describe the tolerability and adverse event profile of daily GDC-0449 administered
orally in combination with daily RO4929097 administered orally for 21 consecutive days.
(Phase Ib) II. To describe the pharmacokinetics of the combination of the combination of
GDC-0449 and RO4929097. (Phase Ib) III. To assess Response Evaluation Criteria In Solid
Tumors (RECIST) 1.1 overall response rates (complete and partial response [CR+PR]) for
combination therapy. (Phase Ib and II) IV. To conduct pharmacodynamic studies in tissue
biopsies (pre- and post-study) for explorative and hypothesis-generating studies. (Phase Ib
and II) V. To assess overall survival. (Phase II) VI. To further describe the
pharmacokinetics and pharmacodynamics of the combination of GDC-0449 and RO4929097 at the
phase II dose at the continuous schedule. (Phase II) V. To conduct pharmacodynamic studies
in tissue biopsies (pre- and post- study drug[s]) for explorative and hypothesis generating
studies. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of gamma-secretase/notch signalling
pathway inhibitor RO4929097 followed by a phase II, randomized, open-label study.


PART A: Patients receive vismodegib orally (PO) once daily (QD) on days 1-21.

PART B: Beginning within 7 days of finishing part A, patients receive vismodegib PO and
gamma-secretase/notch signalling pathway inhibitor RO4929097 PO QD on days 1-21. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II: This is a multicenter study. Patients are stratified according to sarcoma type
(liposarcoma vs non-liposarcoma) and Eastern Cooperative Oncology Group (ECOG) performance
status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gamma-secretase/notch signalling pathway inhibitor RO4929097 PO QD
on days 1-21.

ARM II: Patients receive vismodegib PO and gamma-secretase/notch signalling pathway
inhibitor RO4929097 PO QD on days 1-21.

In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Patients may undergo biopsy at baseline and during the first course of treatment and blood
samples are collected periodically for pharmacokinetic and pharmacodynamic studies.

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

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed sarcoma

- All Patients must have measurable disease as defined by Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- There is a minimum of 1 prior therapy; however, there are no minimum systemic therapy
requirements for well differentiated or de-differentiated liposarcoma, clear cell
sarcoma, chondrosarcoma, alveolar soft part sarcoma and chordomas which have no
effective therapies; for Phase Ib, there are no maximum limits to number of prior
therapies; for Phase II, there is a maximum of 5 prior chemotherapy regimens
including tyrosine kinase inhibitors (TKI); the last dose of systemic therapy
(including TKI) must have been given at least 2 weeks prior to initiation of therapy;
patients receiving nitrosurea (such as BCNU) or mitomycin C must have received their
last dose of such therapy at least 6 weeks prior to initiation of therapy; patients
receiving bevacizumab must wait at least 4 weeks; patients receiving experimental
immunotherapy or antibody based therapies must wait a minimum of 4 weeks or 4
half-lives, whichever is longer; this should be discussed with the Principal
Investigator before registration; tumor biopsies should be performed only after
meeting these requirements; patients should recover to less than Common Terminology
Criteria for Adverse Events (CTCAE) grade 2 toxicities related to previous therapies
to be eligible

- Patients with metastatic or locally advanced (inoperable) gastrointestinal stromal
tumor (GIST) must have progressed on imatinib and sunitinib or be intolerant to both
drugs; the last dose of tyrosine kinase inhibitors imatinib or sunitinib should be
given at least 2 weeks prior to initiation of therapy

- Patients with brain metastasis that have been treated with definitive surgery or
radiation and have been clinically stable for 3 months following the procedure with
no neurological signs or symptoms and no requirement for systemic glucocorticoids are
eligible for study

- Patients must not have current evidence of another malignancy except non-melanoma
skin cancer and superficial bladder cancer

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 9 g/dl

- Platelets >= 100,000/mcL

- Total bilirubin =< upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine amintoransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 X upper limit of normal

- Creatinine =< 1.5 or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with
creatinine levels above 1.5

- Patients treated at Memorial Sloan-Kettering Cancer Center may consent to optional
tumor biopsies before and after initiation of study drug

- Effects of GDC-0449 and RO4929097 on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason and because Hh and Notch signal pathway
inhibitors are known to be teratogenic, 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 study entry, 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; women of childbearing potential are
required to have a negative serum pregnancy test (with a sensitivity of at least 25
mIU/mL) within 10-14 days and within 24 hours prior to the first dose of GDC-0449
and/or RO4929097 (serum or urine); a pregnancy test (serum or urine) will be
administered every 3 weeks to all women of childbearing potential, at the start of
each drug cycle; a positive urine test must be confirmed by a serum pregnancy test;
prior to dispensing GDC-0449 and/or RO4929097, the investigator must confirm and
document the patient's use of two contraceptive methods, dates of negative pregnancy
test, and confirm that patient understands the teratogenic potential of GDC-0449
and/or RO4929097

- Female patients of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period)
for 24 consecutive months.

- The patient is post-menopausal defined by amenorrhea for at least 1 year in
a woman > 45 years old

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

- GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at
concentrations that may be clinically relevant; therefore, caution should be
exercised when dosing GDC-0449 concurrently with medications that are substrates of
CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows; in addition,
GDC-0449 is a substrate of CYP3A4; however, the in vitro metabolic conversion of
GDC-0449 is low; effects of CYP inducers (e.g., carbamezepine, phenobarbital,
phenytoin, rifabutin, rifampin, St. John's wort, and troglitazone) on clinical
concentrations of GDC-0449 are unknown; likewise, the effects of strong inhibitors of
CYP3A4 (e.g., clarithromycin, erythromycin, itroconazole, ketoconazole, nefazodone,
and telithromycin) on GDC-0449 clinical concentrations are unknown, and caution
should be exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4

Exclusion Criteria:

- Patients may not receive other investigational agents within 2 weeks of enrollment in
this study; patients treated with bevacizumab should be off therapy for 4 weeks;
other experimental or immuno therapies should wait for 4 half-lives or 4 weeks,
whichever is longer; prior exposure to Notch or Hedgehog inhibitors is not allowed;
patients who have not recovered to less than CTCAE grade 2 from prior therapies are

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GDC-0449 or RO4929097 used in the study

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible;
patients on warfarin may be considered for enrollment after cessation of warfarin and
appropriate transition to alternate anti-coagulation agents

- Preclinical studies indicate that RO4929097 is a substrate of cytochrome P450
(CYP)3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when
dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors;
furthermore, patients who are taking concurrent medications that are strong
inducers/inhibitors or substrates of CYP3A4 should be switched to alternative
medications to minimize any potential risk; the following medications with strong
potential for interaction are not allowed: indinavir, nelfinavir, ritonavir,
clarithromycin, itraconazole, ketoconazole, nefazodone

- Patients must be able to swallow pills; patients with malabsorption syndrome or other
condition that would interfere with intestinal absorption

- Patients with clinically active liver disease, including active viral or other
hepatitis or cirrhosis, are ineligible

- Patients with uncontrolled electrolyte abnormalities including hypophosphatemia,
hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia or defined as less than the
lower limit of normal for the institution, despite adequate electrolyte
supplementation are excluded from this study

- 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 or other significant cardiac arrhythmias that require
antiarrhythmics or other medications known to prolong corrected QT interval (QTc);
psychiatric illness/social situations that would limit compliance with study

- Pregnant women are excluded from this study because both GDC-0449 and RO4929097 are
agents with potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with GDC-0449 and/or RO4929097 breastfeeding should be
discontinued if the mother is treated with GDC-0449 and/or RO4929097; these potential
risks may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
GDC-0449; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

- Cardiovascular: baseline QTc > 450 msec (male) or QTc > 470 msec (female)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose of gamma-secretase inhibitor RO4929097, defined as the dose level where no more than 1 out of 6 patients experience DLT at the highest dose level below the MAD, graded according to NCI-CTCAE version 4.0 (Phase Ib)

Outcome Time Frame:

Up to 28 days

Safety Issue:


Principal Investigator

Mrinal Gounder

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

Related Keywords:

  • Adult Alveolar Soft-part Sarcoma
  • Adult Angiosarcoma
  • Adult Desmoplastic Small Round Cell Tumor
  • Adult Epithelioid Hemangioendothelioma
  • Adult Epithelioid Sarcoma
  • Adult Extraskeletal Chondrosarcoma
  • Adult Extraskeletal Osteosarcoma
  • Adult Fibrosarcoma
  • Adult Leiomyosarcoma
  • Adult Liposarcoma
  • Adult Malignant Fibrous Histiocytoma
  • Adult Malignant Mesenchymoma
  • Adult Neurofibrosarcoma
  • Adult Rhabdomyosarcoma
  • Adult Synovial Sarcoma
  • Chondrosarcoma
  • Clear Cell Sarcoma of the Kidney
  • Conjunctival Kaposi Sarcoma
  • Dermatofibrosarcoma Protuberans
  • Gastrointestinal Stromal Tumor
  • Metastatic Adult Malignant Fibrous Histiocytoma of Bone
  • Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Metastatic Osteosarcoma
  • Ovarian Sarcoma
  • Recurrent Adult Malignant Fibrous Histiocytoma of Bone
  • Recurrent Adult Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
  • Recurrent Kaposi Sarcoma
  • Recurrent Osteosarcoma
  • Recurrent Uterine Sarcoma
  • Small Intestine Leiomyosarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Stage III Uterine Sarcoma
  • Stage IV Adult Soft Tissue Sarcoma
  • Stage IV Uterine Sarcoma
  • Histiocytoma
  • Histiocytoma, Benign Fibrous
  • Chondrosarcoma
  • Fibrosarcoma
  • Fibrosis
  • Hemangioendothelioma
  • Hemangiosarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Mesenchymoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Sarcoma, Kaposi
  • Sarcoma, Synovial
  • Sarcoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Dermatofibrosarcoma
  • Sarcoma, Clear Cell
  • Sarcoma, Alveolar Soft Part
  • Neurofibrosarcoma
  • Neurilemmoma
  • Hemangioendothelioma, Epithelioid
  • Gastrointestinal Stromal Tumors
  • Desmoplastic Small Round Cell Tumor
  • Histiocytoma, Malignant Fibrous
  • Liver Neoplasms
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral



Memorial Sloan-Kettering Cancer Center New York, New York  10021