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Phase 1 TheraSphere + Everolimus With Neuroendocrine Tumors (NETs) + Liver Only or Liver Dominant Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01864070
Recruitment Status : Withdrawn
First Posted : May 29, 2013
Last Update Posted : July 22, 2014
BTG International Inc.
Novartis Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of the combination of everolimus with TheraSphere that can be given to patients with advanced NETs that have spread to the liver. The safety of everolimus and TheraSphere will also be studied.

Everolimus is designed to block a protein inside the cancer cells, which is also involved in cancer growth.

TheraSphere is a medical device containing a radioactive material called yttrium-90 (Y-90). Tiny glass beads called microspheres are filled with Y-90 and then injected through an artery directly into the liver. This allows a large dose of radiation to be given directly to the tumor, which may lower the risk of side effects from the radiation to other parts of the body and/or to healthy liver tissue. The radiation from TheraSphere stays in the body and begins to lose its effect within 12 days. The glass microspheres will stay in the body from that point on. The radiation will eventually decay (go away). By the time a participant leaves the hospital, the amount of radiation outside of the body will be low enough to not be a threat to others.

Condition or disease Intervention/treatment Phase
Liver Cancer Other: TheraSphere Drug: Everolimus Other: Phone Call Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of TheraSphere and Everolimus Among Patients With Neuroendocrine Tumors and Liver Only or Liver Dominant Disease
Study Start Date : May 2014
Estimated Primary Completion Date : May 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Arm Intervention/treatment
Experimental: TheraSphere + Everolimus

Each cycle is 28 days. Target dose of TheraSphere is fixed at 120 Gy to entire tumor bearing portion of liver given at a single session on Cycle 1 Day 15. The dose of everolimus will be escalated in 2 sequential cohorts of 6 TheraSphere-treated patients each. Starting dose of everolimus is 5 mg by mouth daily for cycles 1 and 2. Patients will receive standard dose of Everolimus at 10 mg PO daily starting cycle 3 day 1.

Once DLT is defined or dose level 2 has been completed, a dose expansion cohort of 10 patients with advanced low to intermediate grade neuroendocrine tumor will be enrolled.

At least 1 time a week by phone or at the clinic for up to 30 days after last everolimus dose, study staff will follow up. Patient asked about any side effects they may have had.

Other: TheraSphere
TheraSphere glass microspheres containing Y-90 injected into catheter, and will deliver 120 Gy to entire tumor bearing portion of the liver given at a single session on Cycle 1 Day 15.

Drug: Everolimus

Starting dose: is 5 mg by mouth daily for cycles 1 and 2. Patients will receive standard dose of Everolimus at 10 mg by mouth daily starting cycle 3 day 1.

Dose Expansion Cohort Starting Dose: Maximum tolerated dose from dose escalation cohort.

Other Names:
  • Afinitor
  • Zortress
  • RAD001

Other: Phone Call
At least 1 time a week by phone or at the clinic for up to 30 days after last everolimus dose, study staff will follow up. Patient asked about any side effects they may have had. The call should last about 10-15 minutes.

Primary Outcome Measures :
  1. Dose Limiting Toxicities (DLT) for Combination of TheraSphere and Everolimus [ Time Frame: 56 days ]
    Dose limiting toxicity (DLT) defined as any toxicity occurring during the first 56 days of therapy with definite, possible or probable attribution to TheraSphere and/or Everolimus and meets CTCAE version 4.0 criteria.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  1. All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.
  2. Patients must have histologically or cytologically confirmed low or intermediate grade neuroendocrine tumor, for which standard curative measures do not exist. Patients with neuroendocrine tumors associated with multiple endocrine neoplasia type 1 (MEN1 syndrome) will be eligible.
  3. Patients must have liver-only or liver-dominant disease.
  4. Patient deemed suitable for TheraSphere therapy after review of anatomic imaging by an Interventional Radiologist.
  5. No prior biliary enteric anastomosis.
  6. Intact portal vein and hepatic artery.
  7. Age >/= 18 years of age.
  8. World Health Organization (WHO) performance status of 0 or 1.
  9. Patients must have normal organ and marrow function as defined below: a) leukocytes >/= 3,000/mcL; b) absolute neutrophil count >/= 1,500/mcL; c) hemoglobin >/= 9 g/dL*; d) platelets >/= 100,000/mcL; e) total bilirubin </= 1.5 X upper limit of normal (ULN); f) AST (SGOT) and ALT (SGPT) </= 1.5 X institutional ULN (5x if liver function test [LFT] elevations due to liver metastases); g) creatinine </= 1.5 X institutional ULN OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal. *Eligibility level for hemoglobin may be reached by transfusion.
  10. The patient must have fasting serum glucose </= 1.3 X upper limit of normal.
  11. Fasting serum cholesterol </= 300 mg/dL OR </= 7.75 mmol/L AND fasting triglycerides </= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
  12. The effects of TheraSphere and everolimus on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use highly effective contraception from the time of study enrollment continuing for the duration of study therapy and for 8 weeks after the last dose of TheraSphere and/or everolimus. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective contraception is defined as either: 1) Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.];
  13. Continuation of # 12: 2) Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment; 3) Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole partner for that subject.]; 4) Use of a combination of any two of the following (a+b or a+c or b+c): a. Use of oral, injected, implanted or other hormonal methods of contraception; b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
  14. Continuation of # 13: In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment. Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must also be advised to use one of the following contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization.
  15. Women of childbearing potential must have a serum pregnancy test within 7 days prior starting study treatment.
  16. Patients must have at least one measurable site of disease according to RECIST in liver.
  17. Patients may have received prior systemic anti-neoplastic therapy. There are no limitations on the number of prior regimens. At least 28 days must have elapsed since last treatment. Prior somatostatin analogs use is allowed. The patients on 3 months of stable dose of concurrent somatostatin analogs will be allowed to continue while on study treatment.
  18. Patients must have international normalized ratio (INR) </= 1.5.

Exclusion Criteria:

  1. Patients may not be receiving any other treatment-related investigational agents.
  2. Uncontrolled intercurrent illness including but not limited to: a) ongoing or active infection requiring parenteral therapy at the time of study registration; b) liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class B or C) Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. Testing required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection; c) symptomatic congestive heart failure resulting in a resting O2 saturation of < 92% on room air; d) unstable angina or pectoris myocardial infarction within 6 months of start of study drug; e) serious uncontrolled cardiac arrhythmia; f) known severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or oxygen saturation that is 88% or less at rest on room air. Pulmonary function test (PFT) is not required at study entry.
  3. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.).
  4. Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study.
  5. Patients who previously received liver directed therapy, with either radiofrequency ablation (RFA), transarterial hepatic embolization (TACE) with or without chemotherapy must have >/= 60 days elapsed since last treatment.
  6. A known history of human immunodeficiency virus (HIV) seropositivity.
  7. Chronic treatment with systemic steroids or another immunosuppressive agent.
  8. Female patients who are pregnant or breast feeding, or of reproductive potential who are not using effective birth control methods.
  9. Patients with a known history of allergic reactions and/or hypersensitivity attributed compounds of similar chemical or biologic composition to everolimus or other rapamycins (sirolimus, temsirolimus).
  10. Known history of brain or leptomeningeal metastases.
  11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study.
  12. Patients who have had hormonal therapy (other than replacement) within 4 weeks prior to entering the study.
  13. Not recovered from adverse events related to previous treatment (excluding alopecia) to active Common Terminology Criteria for Adverse Events (CTCAE) Ver. 4 </= grade 1.
  14. With the exception of tumor common to a single genetic cancer syndrome (ie MEN1, MEN2, von Hippel-Lindau [vHL], tuberous sclerosis complex [TSC] etc), patients with evidence of more than one active malignancy are excluded. Active malignancy is defined as the presence of primary, regional nodal, or distant metastatic neoplasm that has not undergone definitive therapy.
  15. The patient has poorly controlled diabetes mellitus. Patients with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within 1.3 X institutional upper limit of normal and that they are on a stable dietary or therapeutic regimen for this condition.
  16. Patients who have received prior treatment with everolimus or an mTOR inhibitor (sirolimus, temsirolimus, everolimus).

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 identifier (NCT number): NCT01864070

Sponsors and Collaborators
M.D. Anderson Cancer Center
BTG International Inc.
Novartis Pharmaceuticals
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Principal Investigator: Nageshwara V. Dasari, MBBS M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT01864070    
Other Study ID Numbers: 2011-1205
First Posted: May 29, 2013    Key Record Dates
Last Update Posted: July 22, 2014
Last Verified: July 2014
Keywords provided by M.D. Anderson Cancer Center:
Liver cancer
Neuroendocrine tumors
Liver dominant disease
Additional relevant MeSH terms:
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Liver Neoplasms
Neuroendocrine Tumors
Digestive System Neoplasms
Neoplasms by Site
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Digestive System Diseases
Liver Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs