BackgroundEffective therapies for transitional cell carcinoma (TCC) are limited, with objective response rates to most chemotherapeutic regimens below 20%. The purpose of this study was to investigate the biologic activity of combined toceranib phosphate and vinblastine chemotherapy for treatment of TCC. A secondary objective was to compare the utility of Computed Tomography (CT) and abdominal ultrasound (AUS) in tumor response assessments.ResultsDogs with TCC received vinblastine at 1.6 mg/m2 every 2 weeks and toceranib at 2.5–2.75 mg/kg on Monday/Wednesday/Friday. Tumor monitoring was achieved through CT and AUS. Five patients completed the 16-week study. Based on AUS assessments, 3 dogs experienced biologic response to therapy including partial responses (PR, n = 2) and stable disease (SD, n = 1). Based on CT, 5 dogs experienced a biologic response (n = 2 PR, n = 3 SD). Both imaging modalities (ultrasound and CT) were found to provide repeatable measurements between operators, however agreement between operator measurements was greater when CT images were used to assess tumor size.ConclusionsThe combination of toceranib and vinblastine did not result in improved response rates. While agreement in tumor volume assessments between both AUS and CT were excellent between operators, this did not extend to assessment of tumor response. The higher rate of concordance between operators when assessing response to treatment with CT suggests that CT should be considered for future clinical trials involving canine bladder TCC to improve the accuracy and repeatability of tumor measurement. The data suggest that response to therapy as assessed by AUS or CT do not predict duration of clinical response.
Purpose KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications. Experimental Design Cell proliferation, KIT phosphorylation and mast cell degranulation were evaluated in vitro. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase 1 dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities. Results KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n=5 partial response; n=7 stable disease) was observed regardless of KIT mutation status and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The maximum tolerated dose was established as 10 mg/kg. Conclusion KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people.
BackgroundRV1001 is a novel, potent, and selective PI3Kδ inhibitor. The purpose of this study was to evaluate the safety and efficacy of RV1001 in canine Non-Hodgkin lymphoma (NHL).Methods and resultsInhibition of endogenous pAKT by RV1001 in primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in 21 dogs with naïve and drug resistant T and B-cell NHL to assess safety, pharmacokinetic profile, and response to therapy. The objective response rate was 62% (complete response (CR) n = 3; partial response (PR) n = 10), and responses were observed in both naïve and chemotherapy-resistant B and T cell NHL. This study provided the recommended starting dose for a phase II, non-pivotal, exploratory, open label multi-centered clinical trial in 35 dogs with naïve and drug resistant T and B-cell NHL, to further define the efficacy and safety profile of RV1001. The objective response rate in the phase II study was 77% (CR n = 1; PR n = 26). Clinical toxicities were primarily hepatobiliary and gastrointestinal, and were responsive to dose modifications and/or temporary drug discontinuation. Hepatotoxicity was the primary dose limiting toxicity.ConclusionsRV1001 exhibits good oral bioavailability, an acceptable safety profile, and biologic activity with associated inhibition of pAKT in dogs with B and T cell NHL. Data from these studies can be leveraged to help inform the design of future studies involving isoform-selective PI3K inhibitors in humans.
Background: Non-Hodgkin's lymphoma (NHL) is the most common cancer in dogs with over 70,000 new cases diagnosed each year. Evidence suggests that canine NHL is an excellent spontaneous large animal model of human NHL, particularly for the evaluation of new therapeutics. The purpose of this work was to establish the preclinical profile and clinical efficacy of the novel, potent, and selective PI3Kδ inhibitor RV1001 in canine NHL with ultimate goal of informing the development of such inhibitors in human NHL. Methods: Activity of RV1001 on individual PI3K isoforms was determined using a Homogenous Time Resolved Fluorescence assay (Millipore, Billerica, MA). Potency of the compound on the delta isoform was further corroborated in anti-FcϵR1 induced CD63 expression studies using human whole blood. Ability of RV1001 to arrest growth across several cell lines was determined by a MTT assay. Inhibition of endogenous pAKT in cell lines and primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in dogs with T and B naïve and drug resistant NHL to assess safety, pharmacokinetic profile and response to therapy. Results: RV1001 demonstrated significant potency against PI3Kδ (39.3 nM) with several fold selectivity over the α (>250), β (>30), and γ (>20) isoforms. In addition, RV1001 inhibited anti-FcϵR1 induced CD63 expression, a marker of PI3Kδ signaling, in human whole blood basophils with an EC50 of 94.7 nM. Proliferation assays in leukemic cells indicated that the compound arrested growth at concentrations between 1.5 and 13 μM. Reduced PI3Kδ signaling was manifested by a reduction in pAKT with half-maximal inhibition noticed between 10 and 100 nM. Oral administration of 100 mg/kg RV1001 to healthy dogs over a 14-day period resulted in significant accumulation (Cmax = 70 μM on Day 1 versus 186 μM on Day 14; PI3Kδ = 69 μM on Day 14). To date, 9 dogs have been entered into the Phase I clinical trial beginning at a dose of 10 mg/kg SID using a standard 3×3 design. One dog with T cell NHL has had a durable complete response to therapy (10 mg/kg), and 3 additional dogs have had partial responses (15 mg/kg n = 2 and 25 mg/kg n = 1) for an objective response rate of 44%. Adverse events associated with RV1001 administration include grade 1 anorexia and grade 3 and 4 LFT elevation. Pharmacokinetic analyses revealed Cmax concentrations of 10-25 μM with AUC0-t ranging from 50 to 100 μM.hr with accumulation evident after 3-4 weeks of dosing. Exploration of alternative dosing regimens is ongoing to eliminate the drug accumulation and thus circumvent the observed hepatotoxicity. Conclusions: RV1001 exhibits potent activity against PI3Kδ with associated inhibition of AKT phosphorylation, excellent oral bioavailability, and strong single agent efficacy in dogs with both B and T NHL. Data generated from these studies will have broad applicability to the further development of isoform specific PI3K inhibitors in people with NHL. Citation Format: Cheryl A. London, Sarah B. Rippy, Misty D. Bear, Kim Cronin, Andrew H. Abbo, Kumar V. Penmetsa, Srikant Viswanadha, Swaroop Vakkalanka. The novel and selective PI3Kδ inhibitor, RV1001, displays single agent biologic activity in spontaneous canine NHL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2015-4700
<div>Abstract<p><b>Purpose:</b> KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications.</p><p><b>Experimental Design:</b> Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated <i>in vitro</i>. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities.</p><p><b>Results:</b> KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation <i>in vitro</i>. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (<i>n</i> = 5 partial response; <i>n</i> = 7 stable disease) was observed regardless of <i>KIT</i> mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg.</p><p><b>Conclusions:</b> KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. <i>Clin Cancer Res; 23(10); 2565–74. ©2016 AACR</i>.</p></div>
<div>Abstract<p><b>Purpose:</b> KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications.</p><p><b>Experimental Design:</b> Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated <i>in vitro</i>. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities.</p><p><b>Results:</b> KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation <i>in vitro</i>. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (<i>n</i> = 5 partial response; <i>n</i> = 7 stable disease) was observed regardless of <i>KIT</i> mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg.</p><p><b>Conclusions:</b> KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. <i>Clin Cancer Res; 23(10); 2565–74. ©2016 AACR</i>.</p></div>
Chemotherapeutic drugs have been a mainstay of cancer therapy for decades; however, their effectiveness is often hampered by inefficient drug exposures and undesirable toxicity to normal tissues. Here we report on a novel drug delivery system, termed heat shock protein 90 (HSP90) inhibitor-drug conjugates (HDC), based on the property that small molecule inhibitors of HSP90 are preferentially retained in tumors cells in contrast to their rapid clearance from the circulation and normal tissues. By attaching chemotherapeutic drugs to HSP90 inhibitor backbones, HDC technology exploits this inherent retention property to efficiently deliver cytotoxic payloads directly into tumor tissues and provide extended drug exposure. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to the topoisomerase inhibitor SN-38 (active metabolite of irinotecan). In vivo modeling showed that the HSP90 inhibitor moiety was required for tumor-selective retention of STA-12-8666. Prolonged exposure of STA-12-8666 provided extended release of active SN-38 within the tumor compartment, generating up to two weeks of biomarker engagement (γ-H2AX) in contrast to 3-4 days with irinotecan. The broad therapeutic window exhibited by STA-12-8666 conferred superior efficacy and durability over irinotecan treatment alone - resulting in complete or near complete responses (CR) across a broad spectrum of solid tumor models, including an irinotecan-insensitive bladder cancer model and an aggressive lung cancer model where biweekly treatment of STA-12-8666 was initiated at a starting tumor volume 5-times greater that of typical studies. CRs were also observed in a human pancreatic PDX model following 3 doses of STA-12-8666, which were maintained for more than a month. Of note, recurrent PDX tumors remained sensitive to subsequent therapeutic challenge with STA-12-8666 suggesting HDC delivery may circumvent common mechanisms of resistance to irinotecan. Preliminary findings from an ongoing Phase 1 dose escalation study in dogs with spontaneous tumors suggest a well-managed safety profile and encouraging tumor responses. Overall, STA-12-8666 is a promising investigational agent prototypical of a platform technology that can be applied to other cytotoxic payloads to improve therapeutic indices as well as generating new pharmaceutical entities for evaluation as novel anticancer drugs. Citation Format: David A. Proia, Donald L. Smith, Junyi Zhang, Dan Zhou, John-Paul Jimenez, Jim Sang, Sarah Rippy, Cheryl London, Luisa S. Ogawa, Jun Jiang, Teresa Przewloka, Manuel Sequeira, Jaime Acquaviva, Suqin He, John Chu, Chaohua Zhang, Yuan Liu, Josephine Ye, Vladimir Khazak, Igor Astsaturov, Takayo Inoue, Noriaki Tatsuta, Richard C. Bates, Andrew Sonderfan, Dinesh Chimmanamada, Weiwen Ying. STA-12-8666: a first-in-class HSP90 inhibitor drug conjugate (HDC) designed to selectively deliver chemotherapy to tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4409. doi:10.1158/1538-7445.AM2015-4409
<p>Table S1: KTN0158 Dosing Cohorts Table S2: Summary of Anti-KTN0158 Antibody Titers in Dogs with Mast Cell Tumors Following KTN0158 Treatment</p>
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