Michael K.K. Wong

Phase I Pharmacokinetic-Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin (17AAG, NSC 330507), a Novel Inhibitor of Heat Shock Protein 90, in Patients with Refractory Advanced Cancers

Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. Experimental Design: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly × 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot. Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content. Conclusions: 17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly × 3, repeated every 4 weeks.

The high-dose aldesleukin "select" trial: A trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma

Purpose: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2. Experimental Design: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with “good” predictive pathologic features based on an “integrated selection” model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%–33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC. Conclusions: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation. Clin Cancer Res; 21(3); 561–8. ©2014 AACR.

Response to sorafenib after sunitinib-induced acute heart failure in a patient with metastatic renal cell carcinoma: case report and review of the literature.

Cardiotoxicity is an emerging concern with a new class of drugs known as targeted agents, which include trastuzumab and sunitinib. Sunitinib is a small molecule that inhibits multiple tyrosine kinase receptors. This drug was approved by the United States Food and Drug Administration in 2006 for the treatment of clear cell metastatic renal cell carcinoma and advanced gastrointestinal stromal tumors. We describe a 65‐year‐old woman who was treated with sunitinib for metastatic clear cell renal cell carcinoma. After 5 months of therapy, she developed acute heart failure requiring hospitalization; sunitinib was immediately discontinued. The patient had classic symptoms of heart failure, including pleural effusion. An echocardiogram revealed a left ventricular ejection fraction of 30%. She received standard treatment for heart failure, including a β‐blocker, an angiotensin‐converting enzyme inhibitor, and diuretics. Within 1 month, the patients symptoms resolved, and subsequent cardiac evaluation showed that her left ventricular ejection fraction returned to normal. According to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute, her cardiac event associated with sunitinib was defined as grade III toxicity. One month later, sorafenib, another tyrosine kinase inhibitor, was started with the aim of continuing her previous response to sunitinib. After 7 months of sorafenib therapy, the patient had no evidence of heart failure, and her condition was responding to treatment. Clinicians should be aware that sunitinib‐induced heart failure occurs occultly and that many—but not all—cases resolve with discontinuation of the drug. Use of sorafenib after sunitinib‐induced heart failure appears to be safe and effective, which suggests that cardiotoxicity is not a general class effect of the tyrosine kinase inhibitors.

Retrospective Analysis of the Safety and Efficacy of High-dose Interleukin-2 After Prior Tyrosine Kinase Inhibitor Therapy in Patients With Advanced Renal Cell Carcinoma

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

Duration of High-Dose Interferon Alfa-2b Regimen for Resected High-Risk Melanoma

HDI actually utilized. The induction therapy dose was 15 10 6 U/m 2 /d intravenously (IV) for 5 of 7 days for 4 weeks, whereas the standard HDI dose on the ECOG trials is 20 10 6 U/m 2 /d. This was followed by a flat dose of 10 10 6 U subcutaneously (SC) 3 times per week for 48 weeks (as compared to the standard HDI dose of 10 10 6 U/m 2 3 times per week for 48 weeks). Even if one allowed for dose reductions during the induction phase of the ECOG studies to match the lower prescribed dose on the Hellenic trial, the maintenance-phase dose is problematic. The latter has already been shown to be ineffective compared with observation in a large randomized European Organisation for Research and Treatment of Cancer trial (18952) 6 where 10 10 6 U administered SC for 1 year was found to be no better than observation alone. In effect, this nullifies any effect of the SC maintenance phase of the Hellenic trial and reduces this study to a comparison of “induction versus induction,” with all the additional caveats previously discussed. Since adjuvant therapy is given with curative intent, any change in its administration can have significant impact on patients. It is our contention, therefore, that the results of the Hellenic trial cannot and should not be considered conclusive and that the 1-year HDI regimen remain the standard of care for patients with high-risk melanoma as defined in the ECOG trials. The ongoing, high-priority ECOG 1697 trial we are conducting is randomly assigning 1,420 patients with intermediate- and high-risk melanoma to 1 month of IV induction at full standard dosages or to observation, and will shed more light on the issue of whether the induction therapy alone is sufficient for patients in the adjuvant setting.

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIMSM

&NA; ProleukinR Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM) is the largest observational clinical database of high‐dose interleukin‐2 (HD IL‐2)‐treated patients in the US. Herein, the survival and outcome for patients with renal cell carcinoma receiving HD IL‐2 in sequence with targeted therapy are described. HD IL‐2 has an acceptable efficacy and safety profile in current clinical practice and remains a valuable therapy for patients with renal cell carcinoma. Background: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high‐dose interleukin‐2 (HD IL‐2). Patients and Methods: Patients with renal cell carcinoma (n = 352) receiving HD IL‐2 were enrolled in ProleukinR Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015. Results: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL‐2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow‐up, 21 months). Sixty‐one patients had prior TT before HD IL‐2 with an overall response rate (ORR) to HD IL‐2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty‐nine patients received TT only after HD IL‐2 with an mOS of 35.5 months. One hundred forty‐two patients had no TT before or after HD IL‐2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL‐2 without follow‐on TT and 29.7 months in PD patients who received follow‐on TT after HD IL‐2. Conclusions: HD IL‐2 as sole front‐line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL‐2 appear to benefit from follow‐on TT. Patients who progressed on TT and received follow‐on HD IL‐2 experienced major clinical benefit. HD IL‐2 therapy should be considered in eligible patients.

Heart Failure Caused by Molecularly Targeted Therapies for Cancer

Cancer therapeutics is undergoing a revolution with the advent of new drugs that can selectively target molecules responsible for carcinogenesis and tumor growth. The type and mechanism of these targeting drugs vary. Some are small molecules that specifically target a binding site on a receptor or signal transduction molecule. Antibodies have been engineered to bind to the receptors or the corresponding ligands that mediate a critical cancer activity. In almost all cases, the intent is to inhibit or shut down a specific molecular pathway. Unprecedented activity against the cancer is seen without overt traditional toxicities such as alopecia, nausea and/or vomiting, and cytopenias. Unfortunately, an increase in toxicity has now become evident as more experience accumulates with the use of these drugs. In some cases, unexpected cardiotoxicities have arisen when these new drugs have been added to more conventional chemotherapies. Heart failure is the unfortunate manifestation for many of these toxicities. We outline the scope of this problem and examine the mechanisms of drug‐induced heart failure. The distinctive signs and symptoms specific to each drug are described, and the diagnosis and treatment of the condition are discussed. Our aim is to allow the practitioner to recognize the unusual manifestations of heart failure in this setting in order to make a timely diagnosis and begin appropriate treatment measures.

Abstract B140: Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2

Background: The PROCLAIMSM registry (www.proclaimregistry.com), created in 2011, is the largest collection of IL-2 treated patients in the US and provides real-time insights into sequencing or combining IL-2 with new and old therapies and how this may affect patient outcomes. Previously, we reported a median overall survival (mOS) of 20 months with a median follow-up of 37 months in metastatic melanoma (mM) patients treated with high dose IL-2 (HD IL-2) between 2007 and 2012 from a retrospective cohort. These findings led to the hypothesis that improved mOS may have been a result of subsequent salvage therapies, including checkpoint inhibitors. Purpose: To report on the analysis of survival data from 26 sites. Methods: Patients must have received at least one dose of HD IL-2 for this analysis. Those that received checkpoint therapy prior to HD IL-2 were excluded. Statistics and survival analysis on prospectively entered patients were performed on datasets as of March 16th, 2015. Results: The median overall survival (mOS) for the 236 patients was 18.4 months with a median follow-up of 21.7 months. Patients were stratified into three groups; HD IL-2 only (n=123), HD IL-2 followed by ipilimumab (Post ipi, n=78), and HD IL-2 followed by PD-1 inhibitors (Post αPD-1, n=35). There were four patients in the Post αPD-1 group that received anti-PD-L1 treatment. Patients in the HD IL-2 only, Post ipi, and Post αPD-1 groups achieved a mOS of 14, 15.7, and 28.7 months, respectively. The estimated 12-month survival rates were 56%, 64%, and 97%, respectively. There were 10/78 (13%) and 3/35 (8.6%) post therapy treatment-related incidences of autoimmune events in the Post Ipi and Post αPD-1 groups, respectively. No treatment related deaths were reported. Conclusions: This is the first report of clinical data relating to HD IL-2 use followed by checkpoint blockade of the PD-1 pathway. Treatment with anti-PD-1 after initial therapy with HD IL-2 had significantly prolonged survival compared to patients treated with ipilimumab. Moreover, improved survival was not observed in patients treated with follow-on ipilimumab compared to patients treated only with HD IL-2. Anti-PD-1 therapy after HD IL-2, appears to be safe, is therapeutically active. These data support the concept of investigating IL-2 therapy in combination or sequence with newly developed immune checkpoint inhibitors. Citation Format: Michael K.K. Wong, Michael A. Morse, David F. McDermott, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Sandra Aung. Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B140.

A Re-assessment of the Safety and Efficacy of Interleukin-2 for the Treatment of Renal Cell Carcinoma

Interleukin-2 (IL-2) can provide long term durable remissions for patients with advanced or metastatic renal cell carcinoma. The perceived morbidity and the difficulties in delivering this treatment hampered its widespread use in these patients. This review aims to place IL-2 in the modern milieu by reviewing the pharmacology, efficacy and toxicity of this drug. These will be contrasted and compared with the new targeted-agents. The methodology of providing high dose IL-2 treatment, follow-up care and its impact on patient quality of life will be discussed. Importantly, the ability of these agents to provide durable, complete remissions for RCC patients will be placed in context. The goal is to provide the perspective and framework for the reader to balance the important attributes of each of these drugs during the clinical decision making process.