Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

NCT01154452 | Completed Phase 1 Results DMC

• 8 other identifiers: NCI-2011-01412CDR0000680558MSKCC-1004910-0498406N01CM62206P30CA008748U01CA069856
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.

Conditions

Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Unclassified Pleomorphic Sarcoma; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Conjunctival Kaposi Sarcoma; Dermatofibrosarcoma Protuberans; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Unclassified Pleomorphic Sarcoma of Bone; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Kaposi Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Corpus Sarcoma; Small Intestine Leiomyosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Unclassified Pleomorphic Sarcoma of Bone

Outcome Measures

Primary Outcomes (2)

• 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)

  Up to 28 days

• Progression-free Survival (PFS)

  Progression-free survival (PFS) of the combination of RO4929097 with and without GDC-0449 in patients with advanced sarcoma. (Phase II)

  6 weeks

Secondary Outcomes (1)

• Response Rate (CR + PR) as Assessed by RECIST 1.1 (Phase Ib and II)

  Up to 4 months

Study Arms (2)

Arm I (gamma-secretase inhibitor RO4929097)

EXPERIMENTAL

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-21.

Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Arm II (vismodegib and gamma-secretase inhibitor RO4929097)

EXPERIMENTAL

Patients receive vismodegib PO and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-21.

Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Vismodegib

Interventions

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Arm I (gamma-secretase inhibitor RO4929097); Arm II (vismodegib and gamma-secretase inhibitor RO4929097)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (gamma-secretase inhibitor RO4929097); Arm II (vismodegib and gamma-secretase inhibitor RO4929097)

Pharmacological Study OTHER

Correlative studies

Arm I (gamma-secretase inhibitor RO4929097); Arm II (vismodegib and gamma-secretase inhibitor RO4929097)

Vismodegib DRUG

Given PO

Also known as: Erivedge, GDC-0449, Hedgehog Antagonist GDC-0449

Arm II (vismodegib and gamma-secretase inhibitor RO4929097)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed sarcoma
• All Patients must have measurable disease as defined by 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 nitrosourea (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 aminotransferase (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; tumor biopsies should be obtained after fulfilling requirements

You may not qualify if:

• 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 ineligible
• 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, family 3, subfamily A, polypeptide 4 (CYP3A4) 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
• Caution should be exercised when dosing GDC-0449 concurrently with medications that are substrates of cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8), CYP2C9, and CYP2C19 and have narrow therapeutic windows; caution should be exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4
• 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 requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449 and/or RO4929097
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Cardiovascular: baseline QTc \> 450 msec (male) or QTc \> 470 msec (female)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Sarcoma, Alveolar Soft Part; Hemangiosarcoma; Desmoplastic Small Round Cell Tumor; Hemangioendothelioma, Epithelioid; Sarcoma; Chondrosarcoma, Extraskeletal Myxoid; Fibrosarcoma; Leiomyosarcoma; Liposarcoma; Malignant mesenchymal tumor; Neurofibrosarcoma; Rhabdomyosarcoma; Sarcoma, Synovial; Histiocytoma, Malignant Fibrous; Chondrosarcoma; Dermatofibrosarcoma; Gastrointestinal Stromal Tumors; Neuroectodermal Tumors, Primitive, Peripheral; Osteosarcoma; Sarcoma, Kaposi

Interventions

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; HhAntag691

Condition Hierarchy (Ancestors)

Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; Hemangioendothelioma; Hemangioma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Adipose Tissue; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Myosarcoma; Histiocytoma; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Bone Tissue; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Limitations and Caveats

Roche has discontinued further development of the Notch inhibitor (RO4929097) and this Phase II trial was prematurely closed.

Results Point of Contact

• Title: Dr. Mrinal Gounder
• Organization: Memorial Sloan Kettering Cancer Center

gounderm@mskcc.org

646-888-4167

Study Officials

• Mrinal Gounder

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2010
• First Posted: June 30, 2010
• Study Start: June 1, 2010
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: August 15, 2018
• Results First Posted: July 22, 2016

Record last verified: 2018-07

Locations

US (1)