RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer

NCT01058655 | Completed Phase 1 Results DMC

• 1 other identifier: 09-276
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 3

Brief Summary

Research has shown that anti-angiogenic agents can be effective therapies to treat cancer. Anti-angiogenic agents target the blood vessels required for tumors to grow. Vascular endothelial growth factor (VEGF) is one of the cell pathways used for this blood vessel growth. When the investigators interfere with the VEGF pathway, the investigators inhibit this blood vessel growth which is required by tumors. One of the study drugs being used, tivozanib (AV-951), selectively interferes with the VEGF pathway. The second study drug being used, everolimus (RAD001) interferes with the mTOR pathway. The mTOR pathway is another pathway involved in blood vessel and tumor cell growth. By combining these two drugs the investigators hope to slow or reverse tumor cell growth in patients whose tumors have become resistant to other therapies for their disease.

Conditions

Gastrointestinal Cancer

Keywords

Colorectal Cancer

Outcome Measures

Primary Outcomes (4)

• Everolimus Maximum Tolerated Dose (MTD) [Phase I]

  The everolimus MTD in combination with tivozanib is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

  Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.

• Tivozanib Maximum Tolerated Dose (MTD) [Phase I]

  The tivozanib MTD in combination with everolimus is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

  Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.

• Dose Limiting Toxicity (DLT) [Phase I]

  A DLT was defined as a treatment-related (attribution possible, probable, definite) adverse event that meets any of the following criteria: Grade 3 (G3) or higher non-hematologic toxicity (excluding, nausea, vomiting, diarrhea, alopecia, hypertension, hypercholesterolemia, or hypertriglyceridemia); G3 diarrhea, nausea or vomiting lasting \> 48 hours or leading to hospitalization, despite aggressive anti-diarrheal or anti-emetic medications; G4 diarrhea, despite aggressive anti-diarrheal medications; G4 vomiting, despite aggressive anti-emetic medications; G3 hypertension, for which blood pressure cannot be reduced to \<150/100 with anti-hypertensive therapies; G4 hypertension or severe hypertension, as defined by systolic blood pressure \>180 mmHg or diastolic blood pressure \> 110 mmHg; G4 hypercholesterolemia or hypertriglyceridemia lasting \> 7 days, despite appropriate use of anti-hyperlipidemic medications; G4 hematologic toxicity lasting for \>5 days, including leukopenia, neutropen

  Patients were assessed continuously for toxicity while on study. The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.

• Progression-Free Survival (PFS) [Phase II]

  PFS based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the earliest date of last disease assessment. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

  Disease was assessed radiographically to document clinical progression every 2 cycles on treatment. Participants were followed for up to 16 months since study entry.

Secondary Outcomes (2)

• Disease Control Rate (DCR) [Phase II]

  Disease was assessed every 2 cycles on treatment. Median treatment duration on this study cohort was 2 months (range 1-16).

• Overall Survival (OS) [Phase II]

  Long-term follow-up for survival was not specified per protocol. Participants were followed for up to 20 months on this study.

Study Arms (4)

Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg

EXPERIMENTAL

Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.

Drug: Everolimus; Drug: Tivozanib

Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg

EXPERIMENTAL

Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.

Drug: Everolimus; Drug: Tivozanib

Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg

EXPERIMENTAL

Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.

Drug: Everolimus; Drug: Tivozanib

Phase II: Everolimus 10 mg + Tivozanib 1 mg

EXPERIMENTAL

Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.

Drug: Everolimus; Drug: Tivozanib

Interventions

Everolimus DRUG

Also known as: RAD001, Afinitor

Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg; Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg; Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg; Phase II: Everolimus 10 mg + Tivozanib 1 mg

Tivozanib DRUG

Also known as: AV-951

Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg; Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg; Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg; Phase II: Everolimus 10 mg + Tivozanib 1 mg

Eligibility Criteria

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

You may qualify if:

• years of age or older
• Histologic confirmation of a gastrointestinal malignancy, limited to cancer of the esophagus, stomach, small bowel, liver, biliary tract, gallbladder, pancreas, large bowel, appendix, rectum and anus.
• Locally advanced or metastatic disease
• Disease that: a) has recurred or progressed following standard therapy, b) for which no standard therapy currently exists, or c) for which the subject is not a candidate for or unwilling to undergo standard therapy. There is no limit to the number of prior regimens received by the patient.
• ECOG Performance Status of 0, 1 or 2
• Life expectancy of at least 12 weeks
• Adequate organ function as outlined in the protocol
• At least 4 weeks is required from : a) previous regimen of chemotherapy, b) immunotherapy or biological therapy, c) other investigational agents, and d) radiotherapy.
• At least 4 weeks is required from treatment of bevacizumab
• At least 4 weeks is required from prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors
• If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment.

You may not qualify if:

• Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed).
• Clinically apparent CNS metastases or carcinomatous meningitis
• Clinically significant cardiovascular disease
• Major surgery within 4 weeks of the start of study treatment or patients who have not recovered from the side effects of any major surgery.
• Active bleeding diathesis or history of Grade 2 or greater clinically significant bleeding within 3 months of enrollment
• Active infection requiring antibiotics
• Participants with a known positive history of chronic Hepatitis B viral infection or known positive HBV-DNA test are excluded.
• History of interstitial pneumonitis or severely impaired lung function defined as 88% or less O2 saturation at rest in room air
• Immunocompromise or chronic use of immunosuppressant medications
• Uncontrolled serious medical or psychiatric illness
• Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures
• Significant proteinuria, defined as urine dipstick protein of 3+ or greater
• Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy
• Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose
• Patients who are pregnant or lactating

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Beth Israel Deaconess Medical Center: collaborator
• Novartis: collaborator
• AVEO Pharmaceuticals, Inc.: collaborator

Study Sites (3)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Wolpin BM, Ng K, Zhu AX, Abrams T, Enzinger PC, McCleary NJ, Schrag D, Kwak EL, Allen JN, Bhargava P, Chan JA, Goessling W, Blaszkowsky LS, Supko JG, Elliot M, Sato K, Regan E, Meyerhardt JA, Fuchs CS. Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. Oncologist. 2013;18(4):377-8. doi: 10.1634/theoncologist.2012-0378. Epub 2013 Apr 11.

  PMID: 23580238 RESULT

MeSH Terms

Conditions

Gastrointestinal Neoplasms; Colorectal Neoplasms

Interventions

Everolimus; tivozanib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Brian M. Wolpin
• Organization: Dana-Farber Cancer Institute

617.632.6942

Study Officials

• Brian Wolpin, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 29, 2009
• First Posted: January 29, 2010
• Study Start: February 1, 2010
• Primary Completion: September 1, 2013
• Study Completion: April 1, 2015
• Last Updated: April 13, 2017
• Results First Posted: April 7, 2017

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)