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Phase I Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

Phase 1
18 Years
Open (Enrolling)
Hepatic Complications, Liver Cancer

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Trial Information

Phase I Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma



- Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of
temsirolimus and sorafenib in combination in patients with advanced HCC and underlying
liver dysfunction.

Phase I Secondary Objectives

1. Determine safety and toxicity profile.

2. Describe pharmacokinetics of temsirolimus alone and in combination with sorafenib in
cohort of 6 to 9 patients treated at MTD.

3. Observe PFS at 6 months.

Exploratory/Correlative Objectives (To be Combined with Future Phase II Data)

4. Evaluate for tumor necrosis radiographically after 2 cycles of therapy to determine if
there is a relationship with PFS at 6 months in 6 to 9 patients treated in PK cohort at

5. Compare degree of association with proportion with PFS at 6 months between standard
RECIST (version 1.1, see section 11.2) and tumor necrosis measurements after 2 cycles
of protocol therapy.*

6. Measure tumor markers AFP, AFP-L3, and DCP at baseline and after 1 and 2 cycles to
evaluate for any relationship with PFS at 6 months in 6 to 9 patients treated in PK
cohort at MTD.*

7. Measure baseline circulating tumor cell (CTC) levels (high or low) as well as after 1
and 2 cycles of therapy to evaluate for any relationship with PFS at 6 months in 6 to 9
patients treated in PK cohort at MTD.*

8. In patients with known HBV or HCV infection in all dose cohorts, monitor hepatitis
viral load to measure rates of reactivation HBV and/or HCV during and after therapy
with an mTOR inhibitor.

9. Observe PFS at 6 months in patients with HCV, HBV, and other causes of underlying liver

10. Archive blood specimens from consenting patients for future correlative studies.

- These results will be analyzed as part of the future Phase II study of this
combination only for patients in the PK expansion cohort treated at the
recommended Phase II dose.

OUTLINE: This is a multicenter study.

Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and oral
sorafenib tosylate once or twice daily on days 1-28. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic and tumor marker studies.

After completion of study therapy, patients are followed periodically.

Inclusion Criteria

Inclusion Criteria

1. Histologically or clinically* diagnosed AJCC stage II, III, or IV HCC not amenable to
curative resection and with no prior systemic cytotoxic or molecularly-targeted

*Clinical diagnosis is acceptable if tumor is 1-2 cm in size and demonstrates classic
radiographic features of arterial enhancement with venous washout on imaging; if > 2
cm, clinical diagnosis is acceptable if tumor demonstrates these classic radiographic
features and/or AFP > 200 ng/mL.64-65

2. Age ≥ 18 years.

3. Child-Pugh score A or score of B with 7 points only and bilirubin ≤ 2 mg/dL.

4. ECOG performance status ≤ 2 (see Appendix A).

5. Life expectancy greater than 3 months.

6. Radiographically measurable disease 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.

7. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if
completed ≥ 6 weeks prior to study enrollment and if criterion 6 is present.

8. 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.

9. Treatment with appropriate antiviral therapy for patients with active HBV infection
is required.

10. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension
that develops on study is required.

11. Baseline blood pressure must be adequately controlled with or without
antihypertensive medications prior to enrollment (systolic ≤ 140 mm Hg, diastolic ≤
90 mm Hg).

12. Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or
without the use of antihyperlipidemic medications).

13. 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).

14. Adequate baseline organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 75,000/mcL

- Hemoglobin ≥ 8.5 g/dL

- Total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN

- AST(SGOT)/ALT(SGPT) ≤ 5 times ULN

- INR ≤ 1.5 times ULN

- Albumin ≥ 2.8 g/dL

- Creatinine ≤ 1.5 times ULN

15. Able to tolerate oral therapy.

16. Ability to give written informed consent and willingness to comply with the
requirements of the protocol.

17. Women of child-bearing potential must have a negative pregnancy test within 14 days
of study enrollment and must agree to use an effective double method of birth control
during treatment and for three months after receiving their last dose of study drug;
men must be surgically sterile or agree to use an effective double method of birth
control during treatment and for three months after receiving their last dose of
study drug; all patients must notify treating provider immediately if any suspicion
of pregnancy or conception.

18. 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. A list of medications and substances
known or with the potential to interact with selected relevant CYP450 isoenzymes,
P-glycoprotein pathway, and/or UGT1A1 glucuronidation is provided in Appendix B.

Exclusion Criteria

1. Mixed tumor histology or fibrolamellar variant tumors are excluded.

2. Prior antiangiogenic therapy (including thalidomide, sorafenib, sunitinib, or

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 excluded.

8. Patients who have undergone liver transplantation are excluded.

9. Uncontrolled hypertension (> 140/90 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

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 within 6 weeks of enrollment.

15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients on
other forms of anticoagulation may be 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 and fertile women and men who are not willing to comply
with an effective double method of birth control will be excluded.

20. Psychiatric illness, other significant medical illness, or social situation which, in
the investigator's opinion, would limit compliance or ability to comply with study

21. Any other condition that compromises compliance with the objectives and procedures of
this protocol, as judged by the Study Chair, is also grounds for exclusion.

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and recommended phase II dose

Outcome Time Frame:

every 2 months or until progression, approximately 6 months

Safety Issue:


Principal Investigator

Robin-Kate Kelley, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

November 2009

Completion Date:

March 2014

Related Keywords:

  • Hepatic Complications
  • Liver Cancer
  • advanced adult primary liver cancer
  • recurrent adult primary liver cancer
  • adult primary hepatocellular carcinoma
  • hepatic complications
  • localized unresectable adult primary liver cancer
  • Liver Neoplasms
  • Liver Diseases
  • Carcinoma, Hepatocellular



Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois  60611