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Hepatocellular CarcinomaPhase 2NCT01687673

Phase II Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

A Phase 2 study testing Temsirolimus and Sorafenib: in people with Hepatocellular Carcinoma, run by University of California, San Francisco at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 85 years
Conditions the study is for
Hepatocellular Carcinoma
What is being tested?
Temsirolimus and Sorafenib:
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
2 sitesUnited States
Study dates
5 Oct 2012to 9 Jan 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • 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
  • No prior systemic cytotoxic chemotherapy or targeted therapy (including sorafenib) for HCC
  • 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
  • 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.
  • Age ≥ 18 years.
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  • Child-Pugh score of A or B with ≤ 7 points and meeting laboratory eligibility for all parameters
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy greater than 3 months
  • Treatment with appropriate antiviral therapy for patients with active hepatitis B Virus (HBV) infection is required
  • Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension that develops on study is required
  • Baseline blood pressure must be adequately controlled with or without antihypertensive medications prior to enrollment (systolic ≤ 150 mm Hg, diastolic ≤ 90 mm Hg)
  • Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or without the use of antihyperlipidemic medications)
  • 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)
  • 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
  • Able to tolerate oral therapy.
  • 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.
  • 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.
  • 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.
  • mixed histology (mixed HCC-cholangiocarcinoma) tumors if deemed appropriate for HCC therapy by treating MD

Who cannot join

  • Mixed tumor histology or fibrolamellar variant tumors are excluded.
  • 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.
  • Prior treatment with mTOR inhibitor or other molecularly targeted therapy.
  • Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if inclusion criteria are met).
  • Treatment with other investigational agents.
  • Immunosuppressive medications including systemic corticosteroids unless used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or antiemesis
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  • 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.
  • Patients who have undergone liver transplantation are excluded.
  • Uncontrolled hypertension (> 150/90 mmHg).
  • Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300).
  • 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.
  • History of seizure disorder requiring antiepileptic medication or brain metastases with seizures.
  • Serious non-healing wound, ulcer, bone fracture, or abscess.
  • Major surgical procedure less than 4 weeks from start of protocol treatment.
  • 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.
  • 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.)
  • 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).
  • 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.
  • 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.
  • 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
  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Robert H Lurie Comprehensive Cancer Center

    Chicago, Illinois, 60611

  • University of California, San Francisco

    San Francisco, California, 94143

Other trials in United States

About this study

Official title: Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma

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).

Read the detailed description

The hypothesis of this single-arm phase II study is that the combination of temsirolimus and sorafenib will achieve a clinically-meaningful median time to progression (TTP) of at least 6 months, with null hypothesis of less than or equal to 3 months, in first-line systemic therapy for patients with advanced Hepatocellular carcinoma (HCC). A randomized trial would be required to formally compare the efficacy of this combination to sorafenib alone and will be indicated if this phase II study achieves a median TTP of at least 6 months. An interim safety analysis will employ stopping rules after 30% of planned patients have been treated with at least one dose of protocol therapy to ensure the combination does not confer excessive toxicity.

A key aspect of this study will be the requirement of histologic confirmation along with adequate archival tissue for correlative tissue analyses to explore new biomarkers of response to mammalian target of rapamycin (mTOR) inhibition. Circulating biomarker data including enumeration of circulating tumor cells (CTC) and measurement of the tumor marker Alpha-fetoprotein (AFP) will be performed at specific time points to evaluate for predictive value. Specimen banking of tissue, serum, and peripheral blood mononuclear cells will be undertaken to enable future novel biomarker studies. Modified RECIST will be performed in addition to standard RECIST 1.1 to explore for improved imaging predictors of response.

Being tested
Temsirolimus, Sorafenib:
Keywords
Advanced HCC, Temsirolimus, TORISEL, Sorafenib
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TemsirolimusDrug

    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.

  • Sorafenib:Drug

    200 mg tablet twice daily starting on Cycle 1, Day 1 of study enrollment after completion of temsirolimus infusion.

Study groups in NCT01687673
Study groupRoleWhat they receive
TreatmentExperimentalCombination temsirolimus plus sorafenib
Receives: Drug: Temsirolimus; Drug: Sorafenib:

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Median Time to Progression (TTP)

    Median TTP will be calculated in months from date of first dose of protocol therapy to date of removal from study for progression, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of the target lesions (SLD), taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions . Kaplan-Meier methods will be used to summarize the primary endpoint

    Measured: 24 months

Secondary outcomes (8)

  1. Response Rate (RR)

    Response Rate (RR) is defined as any patient whom has a documented complete response (CR) or partial response (PR) per RECIST version 1.1 criteria. Results will be reported by number of participants for each response type: CR or PR.

    Measured: 24 months

  2. Median Progression Free Survival (PFS)

    Median PFS will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, where progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest sum of the SLD recorded since the treatment started and minimum 5 millimeter (mm) increase over the nadir, or the appearance of one or more new lesions for target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Kaplan-Meier methods will be used to summarize time-to-event outcomes.

    Measured: 24 months

  3. Median Overall Survival (OS)

    Median OS for all enrolled patients (intention-to-treat) will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 5 years of follow up post study discontinuation will be censored.

    Measured: 60 months

  4. Time to Treatment Failure (TTF)

    TTF will be measured from date of first dose of protocol therapy to date of study discontinuation for progression, death, or toxicity.

    Measured: 24 months

  5. Number of Patients With a Demonstrated Alpha-fetoprotein (AFP) Response

    In patients with baseline AFP >= 20 ng/mL, AFP response will be measured by the percent change from baseline value to the value at the time of best AFP response. The number of participants with ≥ 50% decline from baseline will be measured.

    Measured: 24 months

  6. Number of Patients Whom Required a Dose Reduction

    The number of patients whom required a dose reduction due to toxicity as classified by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be reported

    Measured: 24 months

  7. Number of Patients Whom Required a Treatment Delay

    The number of patients whom required a treatment delay due to toxicity as classified by the CTCAE version 4.0 will be reported

    Measured: 24 months

  8. Number of Participants Whom Discontinued Treatment Due to Intolerable Toxicity

    The number of participants whom discontinued treatment due to toxicity as classified by the CTCAE version 4.0 will be reported

    Measured: 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Sep 2012 (estimated)
  2. Study start5 Oct 2012
  3. Primary completion26 Apr 2016
  4. Study completion9 Jan 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01687673
Sponsor's protocol ID
124511
Other IDs
NCI-2012-02021
Status last verified
Nov 2020
First submitted
11 Sep 2012
Last updated
7 Dec 2020
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Temsirolimus and Sorafenib: in people with Hepatocellular Carcinoma, run by University of California, San Francisco at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Time to Progression (TTP) (time frame: 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01687673.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2020.

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