Phase II Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Temsirolimus; Sorafenib:
Intervention description: 10 mg weekly will be administered intravenously over 30 to 60 minutes using an infusion pump starting on Cycle 1, Day 1 of study enrollment.; 200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.
Intervention MeSH terms: Sirolimus; Sorafenib; Temsirolimus; MTOR Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Advanced HCC; Temsirolimus; TORISEL; Sorafenib

Summary:

      This Phase II trial is being developed following the completion of a Phase I study of the
      combination of temsirolimus and sorafenib in 25 first-line therapy patients with advanced
      hepatocellular carcinoma (December 2009 through April 2012). The maximum tolerated dose (MTD)
      and recommended phase II dose (RP2D) of the combination of temsirolimus is 10 mg IV weekly
      plus sorafenib 200 mg (oral, twice daily).
    

Eligibility criteria:

        INCLUSION CRITERIA

          1. Patients must have histologically diagnosed American Joint Committee on Cancer (AJCC)
             stage II, III, or IV hepatocellular carcinoma (HCC) not eligible for curative
             resection, transplantation, or ablative therapies

          2. Radiographically measurable disease by RECIST version 1.1 in at least one site not
             previously treated with chemoembolization, radioembolization, or other local ablative
             procedures (i.e. must have at least one measurable target lesion, either within the
             liver or in a measurable metastatic site); a new area of tumor progression within or
             adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is
             acceptable

          3. No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for
             HCC

          4. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if
             completed ≥ 4 weeks prior to study enrollment if patient has recovered with ≤ grade 1
             toxicity and if measurable disease (criterion 2) is present

          5. Prior radiation for bone or brain metastases is permitted if patient is now
             asymptomatic and has completed all radiation and steroid therapy (if applicable) for
             brain or bone metastases ≥ 2 weeks prior to study enrollment.

          6. Age ≥ 18 years.

          7. Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all
             parameters

          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          9. Life expectancy greater than 3 months

         10. Treatment with appropriate antiviral therapy for patients with active hepatitis B
             Virus (HBV) infection is required

         11. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension
             that develops on study is required

         12. Baseline blood pressure must be adequately controlled with or without antihypertensive
             medications prior to enrollment (systolic ≤ 150 mm Hg, diastolic ≤ 90 mm Hg)

         13. Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or
             without the use of antihyperlipidemic medications)

         14. Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7.5%
             (with or without the use of anti-diabetic medications)

         15. Adequate baseline organ and marrow function as defined below

             Adequate bone marrow function:

             absolute neutrophil count > = 1,000/microliter (mcL) platelets ≥ 75,000/mcL hemoglobin
             ≥ 8.5 g/dL

             Adequate hepatic function:

             total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN aspartate aminotransferase (AST) / serum
             glutamic-oxaloacetic transaminase (SGOT) & alanine aminotransferase (ALT) / serum
             glutamic-pyruvic transaminase (SGPT) ≤ 5 X upper limit of normal (ULN) International
             Normalized Ratio (INR) <=1. 5 X ULN

             Adequate renal function:

             albumin ≥ 2.8 g/dL creatinine ≤1. 5 X ULN

         16. Able to tolerate oral therapy.

         17. Ability to understand and willingness to provide informed consent, and the willingness
             to comply with the requirements of the protocol. Informed consent may be obtained with
             the assistance of a medical translator according to institutional policies.

         18. The effects of temsirolimus on the developing human fetus are unknown. For this reason
             and because sorafenib - also being used in this trial - is known to be teratogenic,
             women of child-bearing potential must have a negative pregnancy test within 14 days of
             study enrollment.

             Also, women of child-bearing potential and men must agree to use two methods adequate
             contraception (hormonal plus barrier or two forms of barrier) or abstinence prior to
             study entry and for the duration of study participation. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she needs to inform her treating physician immediately. Men treated or enrolled
             on this protocol must also agree to use adequate contraception prior to the study, or
             be surgically sterile, for the duration of study participation, and for 3 months after
             completion of study drug administration.

         19. Eligibility of patients receiving any medications or substances known to affect or
             with potential to affect the activity or pharmacokinetics of temsirolimus and/or
             sorafenib will be determined following review of the case by the Study Chair. Efforts
             should be made to switch patients who are taking enzyme-inducing anti-convulsant
             agents to other medications.

         20. mixed histology (mixed HCC-cholangiocarcinoma) tumors if deemed appropriate for HCC
             therapy by treating MD

        EXCLUSION CRITERIA:

          1. Mixed tumor histology or fibrolamellar variant tumors are excluded.

          2. Prior systemic or antiangiogenic therapy for HCC (including thalidomide, sorafenib,
             sunitinib, or bevacizumab). Prior systemic therapy for other diagnoses is permitted if
             greater than 6 months have elapsed since last dose, any prior toxicity has recovered
             to ≤ grade 1 by CTCAE v4.0, and treatment was not discontinued for toxicity.

          3. Prior treatment with mTOR inhibitor or other molecularly targeted therapy.

          4. Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if
             inclusion criteria are met).

          5. Treatment with other investigational agents.

          6. Immunosuppressive medications including systemic corticosteroids unless used for
             adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis
             exacerbation (≤ 2 weeks), or antiemesis

          7. Patients with known HIV infection are ineligible due to risk of pharmacokinetic
             interactions between anti-retroviral therapy and the study drugs, as well as potential
             for significant immunosuppression and serious infections with mTOR inhibition.

          8. Patients who have undergone liver transplantation are excluded.

          9. Uncontrolled hypertension (> 150/90 mmHg).

         10. Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300).

         11. Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain
             or bone metastases (if applicable) must be completed ≥ 2 weeks prior to study
             enrollment.

         12. History of seizure disorder requiring antiepileptic medication or brain metastases
             with seizures.

         13. Serious non-healing wound, ulcer, bone fracture, or abscess.

         14. Major surgical procedure less than 4 weeks from start of protocol treatment.

         15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients
             treated with low molecular weight heparin or unfractionated heparin are eligible if on
             a stable dose without evidence of clinically significant bleeding for at least 2 weeks
             prior to enrollment.

         16. Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in
             situ. (Patients with history of malignancy are not considered to have a "currently
             active" malignancy if they have completed therapy and are now considered by their
             physician to be at less than 30% risk for relapse.)

         17. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris,
             uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial
             infarction within preceding 12 months, cerebrovascular accident within preceding 12
             months, pulmonary disease impairing functional status or requiring oxygen, impairment
             in gastrointestinal function that may affect or alter absorption of oral medications
             (such as malabsorption or history of gastrectomy or bowel resection).

         18. Patients will be excluded if there is any history of allergic reaction(s) attributed
             to compounds of similar composition to temsirolimus, sorafenib, their metabolites, or
             any component of their formulation (including excipients and polysorbate 80). This
             includes hypersensitivity to macrolide antibiotics due to potential for
             cross-reactivity with temsirolimus.

         19. Pregnant or lactating women are excluded from this study because temsirolimus and
             sorafenib are drugs with the 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 temsirolimus or sorafenib, breastfeeding
             should be discontinued if the mother is receiving temsirolimus/sorafenib treatment.

         20. Patients who require prohibited medications with potential for serious interactions
             with protocol therapy, and who cannot have therapeutic substitution are excluded.
             Patients receiving any medications or substances that are inhibitors or inducers of
             CYP450 enzyme(s) are ineligible. Lists of prohibited medications and substances known,
             or with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are
             provided in Appendices 6-9 Prohibited Medications

         21. Psychiatric illness, other significant medical illness, or social situation which, in
             the investigator's opinion, would limit compliance or ability to comply with study
             requirements.