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Efficacy and Safety of Everolimus in Patients With Metastatic Colorectal Cancer Who Have Failed Prior Targeted Therapy and Chemotherapy

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ClinicalTrials.gov Identifier: NCT00419159
Recruitment Status : Completed
First Posted : January 8, 2007
Results First Posted : May 16, 2011
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
To assess the safety and efficacy of weekly (70 mg per week) and daily (10 mg per day) everolimus in patients with metastatic colorectal cancer whose cancer has progressed despite prior treatment with targeted therapy and chemotherapy.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Everolimus (RAD001) Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 199 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Multicenter Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Whose Cancer Has Progressed Despite Prior Therapy With an Anti-EGFR Antibody (if Appropriate), Bevacizumab, Fluoropyrimidine, Oxaliplatin, and Irinotecan-based Regimens
Study Start Date : December 2006
Actual Primary Completion Date : March 2009
Actual Study Completion Date : March 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Arms and Interventions
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Arm Intervention/treatment
Experimental: Everolimus (RAD001) 70 mg/week Drug: Everolimus (RAD001)
Everolimus was supplied in 5 mg tablets in blister packs.
Other Names:
  • Afinitor
  • Zortress
  • Certican
Experimental: Everolimus (RAD001) 10 mg/day Drug: Everolimus (RAD001)
Everolimus was supplied in 5 mg tablets in blister packs.
Other Names:
  • Afinitor
  • Zortress
  • Certican


Outcome Measures
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Primary Outcome Measures :
  1. Disease Control Rate (DCR) and Objective Response Rate (ORR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Imaging every 8 weeks ]

    RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stable") or worsen ("progression") during treatments.

    Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease)and Objective Response Rate (ORR) defined as the percentage of participants with best overall Objective Response (complete response or partial response).


  2. The Number of Participants With Best Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Imaging every 8 weeks ]

    RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stable") or worsen ("progression") during treatments.

    Best Over Response (BOR): Complete Response (CR, No lesions), Partial Response (PR, 30% decrease in lesions), and Stable Disease (SD, none of the above)



Secondary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Imaging every 8 weeks ]
    Duration in months from the date of first study treatment to the date of the first documented disease progression or death due to any cause.

  2. Overall Survival (OS) [ Time Frame: Every 3 months ]
    Overall survival defined as the time from date of first study treatment to the date of death due to any cause.

  3. Number of Patients Who Died, Had an Serious Adverse Event (SAE), Had Grade 3 to 4 Adverse Event (AE), Discontinued Due to an AE, or Had a Clinical Notable AE by Treatment (tr). [ Time Frame: From the first day of treatment until 28 days after discontinuation of study treatment ]
    Toxicity assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAEv3.0). On treatment death defined as deaths occurring no more than 28 days after the discontinuation of study treatment.

  4. Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 70 mg/Week [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  5. Biomarker Predictive of Clinical Benefit (DCR by KRAS) on Everolimus (RAD001) 10 mg/Day [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable compared in this biomarker analysis is disease control rate (DCR) within the 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  6. Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS ) on Everolimus (RAD001) 70mg/Week [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  7. Biomarkers Predictive of Clinical Benefit (Median PFS and OS by KRAS) on Everolimus (RAD001) 10mg/Day [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis are Median progression free survival (PFS) and overall survival (OS) within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: KRAS gene mutation. From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  8. Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 70mg/Week [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 70mg/week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  9. Biomarkers Predictive of Clinical Benefit (DCR by PTEN ) on Everolimus (RAD001) 10mg/Day [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis is DCR within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  10. Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 70mg/Week [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 70mg/Week arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.

  11. Biomarkers Predictive of Clinical Benefit (Median PFS and OS by PTEN ) on Everolimus (RAD001) 10mg/Day [ Time Frame: Screening and Day 1 of cycles 2, 3, 4 and end of treatment ]
    The efficacy variable that was compared in the biomarker analysis are PFS & OS within the Everolimus (RAD001) 10mg/day arm in the analysis not adjusted for prognostic factors: from archival tumor tissue (and additionally from a biopsy at a metastatic site, if available), collected during screening: PTEN loss (imunohistochemistry, IHC), phosphoAKT (IHC), phosphoS6 (IHC), and p53 (IHC). From blood plasma, collected at screening then on day 1 at cycles 2, 3 and 4, and at the end of treatment: blood lactate dehydrogenase (LDH) isoenzyme fractionation and serum levels of sVEGFR2, bFGF, PLGF and VEGF.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Age ≥ 18 years old.
  • Patients with metastatic colorectal cancer (CRC).
  • Patients must have sufficient and obtainable tumor tissue for biomarker analysis from original surgical resection.
  • Patients with documented disease progression within 6 months of their most recent dose of chemotherapeutic regimens.
  • Patients with at least one measurable lesion.
  • Adequate bone marrow function.
  • Adequate liver function.
  • Adequate renal function.
  • Patients with a life expectancy of > 3 months.
  • Patients with a World Health Organization (WHO) performance status of 0, 1, or 2.
  • Women of childbearing potential must have had a negative serum pregnancy test 72 hours prior to the administration of the first study treatment.
  • Patients who give a written informed consent obtained according to local guidelines.

Exclusion criteria:

  • Patients currently receiving anti-cancer agents or who have received these within 4 weeks prior to study entry.
  • Patients who have previously received RAD001.
  • Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients.
  • Chronic treatment with steroids or another immunosuppressive agent.
  • Patients with untreated central nervous system (CNS) metastases or neurologically unstable CNS metastases.
  • HIV seropositivity.
  • Patients with an active, bleeding diathesis. Patients may use enoxaparin.
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.
  • Patients who have a history of another primary malignancy < 3 years, with the exceptions of non-melanoma skin cancer, and carcinoma in situ of uterine cervix.
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods.
  • Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to first study treatment.
  • Patients unwilling to or unable to comply with the protocol.

Other protocol defined inclusion/exclusion criteria may apply

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00419159


Locations
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United States, Nevada
Nevada Cancer Institute
Las Vegas, Nevada, United States, 89135
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Additional Information:

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00419159    
Other Study ID Numbers: CRAD001C2241
First Posted: January 8, 2007    Key Record Dates
Results First Posted: May 16, 2011
Last Update Posted: April 23, 2019
Last Verified: April 2019
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Colorectal cancer
metastatic colorectal adenocarcinoma
anti-EGFR antibody
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
 Colonic Diseases
Intestinal Diseases
Rectal Diseases
Everolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs