R. Bahleda

Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors

BACKGROUND Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Tumour growth rates and RECIST criteria in early drug development.

PURPOSE The evaluation of treatment efficacy with RECIST criteria does not take into account tumour growth dynamics. We notably investigated the impact of the pre-treatment tumour growth rate (GR) on the evaluation of treatment response. PATIENTS AND METHODS Seventy-six patients included in phase I clinical trials had scanographic evaluations before and after starting an experimental treatment. The GR was calculated for the pre-treatment period and for the experimental period (i.e. during the new treatment). Tumour response was evaluated per protocol at week 12 and at week 24 of the experimental period according to RECIST criteria. We studied the relation between pre-treatment and experimental GRs and RECIST tumour response. RESULTS On average the tumour GR was decreased by 40% during the experimental period; compared to the pretreatment period (p=0.03). An increased growth rate (acceleration of GR during experimental treatment compared to pretreatment) was observed in 20 (38%) of the 53 patients considered as non-progressive at week 12 according to RECIST. Conversely a decreased GR was observed in 12 out of 23 (53%) patients classified as progressive according to RECIST. The variation in the GR between the pre-treatment and experimental period was not significantly correlated with response evaluated according to RECIST at week 12 or at week 24 (p=0.45 and 0.44, respectively). CONCLUSIONS RECIST evaluation of tumour response depends on the natural history of the tumours and poorly measures the impact of treatment on the kinetics of tumour growth. Integrating pre-treatment GR evaluations could substantially improve the assessment of treatment efficacy in drug development.

Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors

BACKGROUND Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments. PATIENTS Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m(2) (B) docetaxel, 1250 mg/m(2) gemcitabine/100 mg erlotinib (C1), or 60 mg/m(2) doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3. RESULTS Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m(2) gemcitabine/75 mg erlotinib) and D2 (50 mg/m(2) doxorubicin). Grade 3-4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ≥12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ± 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 ± 21 ng/ml with disease control (P < 0.001). CONCLUSION AVE1642 was tolerable with 75-100 mg/m(2) docetaxel and 1000 mg/m(2) gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response.

A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.

Pemetrexed-Induced Pneumonitis: A Case Report

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors

BACKGROUND This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. METHODS In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. RESULTS Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. CONCLUSION Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.

Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven

BACKGROUND The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side-effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). CASE PRESENTATION We describe four cases of patients with cancer who developed AKI after starting mTOR inhibitor therapy. A kidney biopsy showed acute tubular necrosis (ATN) with prominent tubular dysfunction. Withdrawal of the drug leads to a rapid recovery in two cases. However, a fixed renal dysfunction was noted in the other two cases, one of which will remain dialysis-dependent. Such patients lead to a broad differential diagnosis of AKI including prerenal AKI, ATN, cancer-related GN, and drug-induced acute interstitial nephritis. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. CONCLUSIONS ATN have not been reported with mTOR inhibitor use. These cases demonstrated a potentially new and serious adverse consequence occurring with the use of an mTOR inhibitor, of which physicians need to be aware.

Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients IL-2 interferes with the pharmacokinetics of imatinib mesylate

Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.

Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer

BACKGROUND This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. RESULTS Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. CONCLUSION In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. EUDRACT N 2007-001698-27.BACKGROUND This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy. RESULTS Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. CONCLUSION In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. EUDRACT N 2007-001698-27.

Abstract C197: A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors

Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical xenograft models, the oral selective Class I PI3K inhibitor XL147 augments the anti‐tumor efficacy of EGFR inhibitors, including erlotinib. Methods: Patients (pts) with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL147 in combination with erlotinib. Erlotinib is dosed qd, and XL147 is dosed once daily on Days 1–21 of each 28‐day cycle. Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated every 8 weeks. Results: As of 01 Aug2009, 18 pts with advanced solid tumors have been enrolled: NSCLC (7), CRC (5), HCC, HNSCC, biliary tract, carcinoid, ethmoid, and esophageal cancer (1 each). Pts have been treated at 6 dose levels up to 400 mg XL147/150 mg erlotinib. No DLTs or study treatment‐related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs were rash (40%), fatigue (30%), diarrhea, nausea, and vomiting (each 20%). Two events of Grade 3 thrombosis (both unrelated) were reported. Based on preliminary data, the PK of XL147 in combination with erlotinib is consistent with that observed for XL147 given alone (Exelixis Study XL147‐001). Likewise, XL147 does not appear to alter the PK of erlotinib as the PK parameters of erlotinib are similar to published single agent values. Modulation of PI3K pathway and EGFR signaling by XL147/erlotinib has been demonstrated in PBMCs by reductions in phosphorylation of AKT, the AKT substrates PRAS40 and GSK3 , and ERK. In skin and tumor biopsies, robust post‐dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, ERK, and EGFR. For example, in tumor biopsies from a subject with an ethmoid tumor (400 mg XL147/150 mg erlotinib), reductions in pAKT‐T308 (43%), p4EBP1 (44%), pERK (43%), and pEGFR (40%) were evident at Day 15 post‐dose, with a corresponding reduction in Ki67 (47%) and induction of apoptosis (2.7‐fold). One EGFR inhibitor‐naive NSCLC pt (no EGFR mutations detected in archival tumor sample, 200 mg XL147/150 mg erlotinib) had a confirmed PR with a 59% reduction in the sum of target lesions. Nine pts continued on study ≥ 12 weeks, including 2 pts who remained on study ≥ 24 weeks. Conclusions: The combination of XL147 and erlotinib is generally well tolerated at doses up to 400 mg XL147/150 mg erlotinib, with no apparent drug‐drug PK interaction or emergent toxicities, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C197.