Andrew Strahs

Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

PURPOSE Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigators choice single-agent therapy in relapsed or refractory disease. PATIENTS AND METHODS In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigators choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. RESULTS Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigators choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigators choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigators choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigators choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. CONCLUSION Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigators choice therapy in patients with relapsed or refractory MCL.

Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer

PURPOSE Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. PATIENTS AND METHODS This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). RESULTS Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). CONCLUSION Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.

Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial

PURPOSE Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. RESULTS A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). CONCLUSION Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.

Analysis of PTEN and HIF‐1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon‐α

Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon‐α (IFN).

Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy

The central role played by the class IA phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with “PI3K activated” tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize “PI3K activated” tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into “pathway on” and “pathway off” subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific “pathway on” patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.

Q-TWiST Analysis of Patients Receiving Temsirolimus or Interferon Alpha for Treatment of Advanced Renal Cell Carcinoma

AbstractBackground and Objective: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-α or the combination of these agents, using data from a phase III clinical trial. Methods: Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment. Results: All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNα (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer qualityadjusted survival in terms of Q-TWiST than those receiving IFNa (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNα) and IFNα groups were not statistically significant.Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states. Conclusion: Temsirolimus resulted in significantly longer Q-TWiST (qualityadjusted survival) in patients with advanced RCC than IFNα therapy.

A Phase Ib Study of the VEGF Receptor Tyrosine Kinase Inhibitor Tivozanib and Modified FOLFOX-6 in Patients With Advanced Gastrointestinal Malignancies

BACKGROUND Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. PATIENTS AND METHODS Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. RESULTS Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. CONCLUSION Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.

A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 μg of recombinant human interleukin‐12 (rhIL‐12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL‐12 were evaluated. Recombinant human IL‐12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu‐like symptoms, which exhibited a dose‐response relationship. Pharmacokinetic analysis suggested that serum IL‐12 levels increased with dose. Analysis of serum levels indicated that interferon‐γ increased with the dose of rhIL‐12, whereas IL‐6 levels showed no changes with rhIL‐12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL‐12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon‐γ and signal transducer and activator of transcription are biomarkers of rhIL‐12 activity.

Abstract C123: A phase 1 study to evaluate the absorption, metabolism, and excretion of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) tivozanib.

Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3. Tivozanib has demonstrated antitumor activity in a Phase II study in subjects with renal cell carcinoma. This study was conducted to determine the absorption, metabolism, and excretion of a single 1.5 mg dose of [14C]-tivozanib administered to healthy male subjects. Methods: This study was approved by an independent institutional review board and enrolled 8 healthy male subjects; each received a single 1.5 mg (∼160 μCi) dose of oral [14C]-tivozanib. Whole blood, serum, urine, and feces were collected for up to 28 days post dose for assessment of total radioactivity and/or for determination of [14C]-tivozanib concentrations. All subjects were kept confined as inpatients for the duration of the study. Safety assessments included laboratory tests, electrocardiograms, physical examinations, vital signs, and recording of adverse events. Pharmacokinetic data were analyzed by noncompartmental methods. Results: Subjects had a mean age of 32 years (range 19 to 46 years) and mean body mass index of 25 kg/m2 (range: 23 to 29 kg/m2). Of the 8 subjects enrolled, 7 completed the study. [14C]-tivozanib and total radioactivity were slowly absorbed and eliminated from serum; median Tmax was 10.0 hours, and mean (±SD) t1/2 for [14C]-tivozanib and total radioactivity in serum was 89.3 hours (± 23.5 hours) and 99.1 hours (± 32.5 hours), respectively. Mean (±SD) Cmax and AUC0−∞ values for [14C]-tivozanib were 12.1 ng/mL (±46.9 ng/mL) and 1084 ng*hr/mL (±417 ng*hr/mL), respectively; these values were approximately 93% and 80% of the values for total radioactivity in serum, respectively. Mean blood to serum concentration ratios ranged from 0.495 to 0.615 through 312 hours post dose, indicating minimal association of radioactivity with red blood cells. Overall, mean (±SD) recovery of total radioactivity was 91.1% (±11.0%), with 11.8% (±4.6%) recovered in urine and 79.3% (±8.8%) recovered in feces. No unchanged tivozanib was found in the urine. A single therapeutic dose of tivozanib was well tolerated in healthy subjects. Conclusion: These results indicate that after an oral dose of 1.5 mg (∼160 μCi) of [14C]-tivozanib, the majority of circulating drug in the systemic circulation was unchanged tivozanib. The main route of elimination of [14C]-tivozanib was via feces, with at least 11.8% of the administered total radioactive dose being absorbed into systemic circulation. No unchanged tivozanib was found in the urine, indicating that tivozanib does not undergo renal excretion. In this study, the mean half-life of [14C]- tivozanib was 89.3 hours, one of the longest half-lives among VEGF TKIs. Tivozanib is currently being tested in a Phase III study in subjects with RCC and Phase I/II studies in other solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C123.

A Phase I cardiac safety and pharmacokinetic study of tivozanib hydrochloride in patients with advanced solid tumors

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half‐life. Tivozanibs effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.5 mg of tivozanib orally, once daily, for 21 days. Safety evaluations, serial blood samples for pharmacokinetic measurements, and time‐matched, triplicate, 12‐lead electrocardiograms (ECG) were collected. Fifty patients were evaluable. The maximum change in QTcF was 9.3 milliseconds (90% confidence interval [CI] 5–13.6), occurring 2.5 hours after dosing on Day 21. The central tendency change across all time points was +2.2 milliseconds. The slope of the exposure–ΔQTcF relationship was 0.08464 ms/ng/mL, with a predicted QTcF change of 8.27 milliseconds at the average tivozanib Tmax of 118.1 ng/mL (upper CI 12.6 milliseconds). There were no QTcF values >500 milliseconds or significant changes from baseline observed in heart rate, PR interval, and QRS complex. These data, evaluated along with other tivozanib preclinical and clinical study results, suggest that administration of 1.5 mg tivozanib for 21 days has a minimal effect on cardiac repolarization or ECG morphology in oncology subjects.