Craig Devoe

Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated. Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated. Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for “high”-HA patients (n = 6), and 3.5 and 5.7 months for “low”-HA patients (n = 11), respectively. Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848–54. ©2016 AACR.

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patients own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.

Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Abstract CT012: Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors (NCT02157792):

Background: ATR is a regulator of the cellular response to replication stress, where it signals DNA damage repair through the homologous recombination pathway. Many cancer cells depend on ATR to survive DNA damage. VX-970 is a potent, selective inhibitor of ATR with marked preclinical anticancer activity in combination with DNA-damaging chemotherapy in preclinical models. Methods: Pts received intravenous VX-970 in combination with Cis using a 3+3 dose escalation design. Cis was administered on day 1 and VX-970 on days 2 and 9 in 21-day cycles. Results: 28 pts were treated (12 M/16 F); median age 62.5 yrs (range 28-79 yrs) and ECOG PS 0-1. Primary tumors were colorectal (n = 5), breast (n = 4), ovarian (n = 3), pancreatic (n = 2), and other cancers (n = 14). Non-DLT grade 3-4 treatment-related adverse events occurred in 11 pts, including nausea, cytopenias, hypotension, hypoalbuminemia, hypokalemia, elevated LFTs, and drug hypersensitivity. Maximum tolerated combination dose was not reached; dose escalation was stopped because pharmacokinetic (PK) exposures of VX-970 at 140 mg/m2 exceeded levels previously shown in preclinical models to result in robust target engagement and tumor regression in combination with Cis. There was no effect of Cis on VX-970 PK. Terminal elimination half-life was ?16h and PK was proportional across the dose range. Among pts who received VX-970 at 140 mg/m2 with Cis, preliminary results showed RECIST partial responses in 4 pts: 3 platinum-resistant/refractory (mesothelioma, ovarian and TNBC) and 1 ongoing unconfirmed response in a pt in which platinum sensitivity is currently unknown (neuroendocrine prostate cancer). Conclusions: The recommended phase 2 dose is VX-970 140 mg/m2 and Cis 75 mg/m2 with RECIST antitumor responses observed including platinum-refractory/resistant pts. Combination studies involving pts with biomarker-defined NSCLC (gemcitabine) and TNBC (platinum) are ongoing. Citation Format: Geoffrey Shapiro, Robert Wesolowski, Mark Middleton, Craig Devoe, Anastasia Constantinidou, Dionysis Papadatos-Pastos, Marjorie Fricano, Yanqiong Zhang, Sharon Karan, John Pollard, Marina Penney, Mohammed Asmal, F. Gary Renshaw, Scott Z. Fields, Timothy A. Yap. Phase 1 trial of first-in-class ATR inhibitor VX-970 in combination with cisplatin (Cis) in patients (pts) with advanced solid tumors (NCT02157792). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT012.

Immune Checkpoint Inhibitors in the Cancer Patient with An Organ Transplant

The use of immune checkpoint inhibitors (ICI) in several cancers is expanding; however, their use in patients with cancer and an organ transplant is very limited. In this review, we summarize the literature and the experience of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) inhibitors in the organ transplant patient. The immunology of CTLA-4 and PD-1 inhibitors and their role in tolerance breakdown is also reviewed. While CTLA-4 inhibitors have been successfully used in kidney, liver, and heart transplant patients without rejection, the uses of PD-1 inhibitors and the combination therapy of CTLA-4 and PD-1 inhibitors have been associated with cellular- and antibody-mediated rejection. While immunosuppression minimization is needed for ICI to provide the best response when managing transplant patients who develop malignancy, this can lead to rejection episodes. Prevention strategies, such as the use of ongoing steroids and sirolimus, could prevent rejection while sustaining tumor response. As the experience grows with these agents, we will learn more about tolerance and the use of ICI in the organ transplant patient. Therefore, the use of an immune checkpoint blockade in transplantation is extremely difficult, and future research should focus on finding the right balance between unleashing the immune system to provide an anti-tumor effect but at the same time sustaining tolerance so that rejection is suppressed. Also, the ability to identify biomarkers that may predict rejection early and allow for the fine tuning of doses and frequencies of drug administration would be very helpful.

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture–based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881–90. ©2018 AACR.

A case of acute kidney injury from crystal nephropathy secondary to pomalidomide and levofloxacin use

Pomalidomide is an analog of thalidomide with immunomodulatory, anti-angiogenic, and anti-neoplastic activity indicated for the treatment of multiple myeloma refractory to at least two prior therapies. The incidence for renal failure was <5% in a single phase II study of pomalidomide and dexamethasone in patients with multiple myeloma that failed both lenalidomide and bortezomib therapy. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury in pomalidomide and fluoroquinolone use.

BRAF inhibitors - do we need to worry about kidney injury?

The discovery of mutations in BRAF has led to an era of targeted therapies which are clinically used in patients with malignant melanoma, colorectal cancer, lung cancer, and hairy cell leukemia.[1–7] Signals from the surface of the cell are transmitted to the DNA, via a chain of proteins, namely the mitogen-activated protein kinase/extracellular signalregulated protein kinase (MAPK/ERK). Included in the MAPK pathway are the BRAF, MEK proteins, which in turn serve as ‘on ’or ‘off’ switches for various cellular signals. BRAF mutations lead to constitutive activation of the MAPK pathway, resulting in enhanced gene transcription, cellular proliferation, and oncogenic activity.[2] The most common mutation encountered in patients with melanoma is V600E. Discovery of this mutation leads to the approval of vemurafenib and dabrafenib for the treatment of BRAF V600-mutated melanomas by the US Food and Drug Administration (FDA) as well as the European Medicines Agency. Majority of the clinical trials and published literature with these agents are in the use of mutated melanomas. Vemurafenib, the first selective BRAF inhibitor, was evaluated in clinical trials for melanoma. In a phase III trial [4] comparing vemurafenib with dacarbazine, patients in the vemurafenib group had a decreased risk of progression (hazard ratio [HR]: 0.26; p < .001) and death (HR: 0.37; p < .001), leading to the regulatory approval of vemurafenib. Dabrafenib, another BRAF inhibitor, was subsequently developed and showed similar activity to vemurafenib. A phase III clinical trial in melanoma patients compared dabrafenib with chemotherapy; this study demonstrated a 53% objective response rate for the dabrafenib group and improved progression-free survival (HR: 0.3; p < .001).[7] BRAF mutations are also found in other cancers and this form of targeted therapy is being considered in various hematologic and oncologic malignancies. Is there renal toxicity? While most of these agents are known to cause dermatologic toxicities, knowledge of renal toxicities of BRAF inhibitors is limited. Given the wide use of these agents in other cancers, it is important that data on nephrotoxicities are available to clinicians to review. In the initial phase III trials of vemurafenib, there was no renal toxicity reported with this drug.[4] In 2013, in a letter to the editor, Uthurriague et al. [8] were the first to report acute kidney injury (AKI) with this drug. In their cohort of 16 patients, 15 developed a moderate decrease in the glomerular filtration rate (GFR) within 1 month of starting treatment which persisted during the course of the treatment. In addition, five patients developed proteinuria. In a case report published by Regnier-Rosencher et al.,[9] they reported four cases of AKI associated with severe cutaneous drug reactions related to vemurafenib. Two of these patients were also noted to have peripheral hypereosinophilia. In three patients, stopping the vemurafenib leads to resolution of both the skin rash and the AKI. In one patient, vemurafenib dose was reduced and reintroduced. This again led to worsening renal function without reoccurrence of the rash. None of the patients in this series underwent a kidney biopsy. Launay-Vacher et al. [10] published a case series of eight patients from a registry in France. One patient in this series had a kidney biopsy, which revealed acute tubular necrosis. On reviewing the above cases reported thus far,[8–10] it appears that males may be more susceptible to develop renal toxicity with this agent compared to women. Also, patients with underlying kidney disease (chronic kidney disease [CKD] stage 2 or higher) may be at a higher risk than people with normal renal function. Unpublished work by Muzet et al. [11] was presented at a conference in 2015 in Europe. They conducted a retrospective study of 74 patients with metastatic melanoma treated with vemurafenib. The mean duration of treatment was 10 months and cases of AKI were noted more often in men than in women. A total of three kidney biopsies were done in this study and they showed tubular toxicity and interstitial fibrosis. One biopsy showed focal, noninflammatory, and discrete lesions of interstitial fibrosis 7 months after the first observation of AKI. The two others performed less than 3 months after AKI showed chronic tubular and interstitial lesions with acute tubular necrosis. Changes were chronic in two of the three cases.[11] We had reviewed the FDA Adverse Event Reporting System’s (FAERS) quarterly legacy data file from the third quarter of 2011 to the second quarter of 2014 for vemurafenib.[12] A total of 132 cases of AKI were reported secondary to vemurafenib to the FAERS in the time frame reviewed. Eightyfive patients were men and 47 women (p < 0.01). Average age of the men was 65 years and 59 years for the women (p < 0.01). Fourteen cases of electrolyte disorders were reported (hypokalemia-6 cases and hyponatremia-8 cases).

PEG-asparaginase induced severe hypertriglyceridemia

Asparaginase (ASP) is an effective chemotherapy agent extensively used in children with acute lymphocytic leukemia (ALL). There has been a recent interest in using ASP in adults with ALL, particularly the less toxic pegylated (PEG) formulation. Hypertriglyceridemia (HTG) is a rare complication of PEG-ASP therapy. We report two cases of obese patients who developed severe HTG after receiving PEG for ALL. Both patients were incidentally found to have severe HTG (TG of 4,330 and 4,420 mg/dL). In both patients, there was no personal or family history of dyslipidemia or hypothyroidism. There was no evidence of pancreatitis or skin manifestations of HTG. Both patients were treated with PEG cessation, low-fat diet and pharmacotherapy. Both patients were re-challenged with PEG, with subsequent increase in TG but no associated complications. TG returned to baseline after discontinuing PEG and while on therapy for HTG. A literature review of PEG-induced HTG in adults demonstrated similar results: asymptomatic presentation despite very severe HTG. HTG is a rare but clinically important adverse effect of PEG. Underlying obesity and/or diabetes may represent risk factors. Clinicians should monitor TG levels during PEG therapy to avoid TG-induced pancreatitis.

Sequential development of two separate therapy-related myeloid neoplasms following radiotherapy for prostate cancer

Therapy-related myeloid neoplasm (t-MN) is a newly defined entity in the 2008 World Health Organization (WHO) classification and includes therapy-related acute myeloid leukemia (t-AML), myelodysplatic syndrome (tMDS) and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN).[1] Its incidence is rising due to prolonged survival following effective treatments for prior malignancies. Ionizing radiation is a known carcinogen. Risks for AML and MDS are known to increase after radiation therapy for primary cancers.[2] The estimated incidence of t-MN in prostate cancer patients definitively treated with radiation therapy is 0.15% for AML [3] and 0.5% for MDS.[4] We report an extremely rare case with two separate t-MNs (therapy-related acute promyelocytic leukemia (t-APL) and t-MDS/AML) that sequentially developed following radiotherapy for prostate cancer. The patient was a 79-year old male who received external beam radiation therapy (EBRT) and brachytherapy for prostate cancer in 2007. Three years later he was admitted with syncope due to bifascicular cardiac block. Complete blood count (CBC) revealed pancytopenia (hemoglobin 6.5 g/dL, platelets 14 10/L, and white blood cells 0.6 10/L). Bone marrow aspirate was hemodilute, but revealed a small population of atypical promyelocytes. Flow cytometric analysis showed that the atypical promyelocytes were positive for CD33, CD13, CD117 and negative for human leukocyte antigen (HLA)-DR and CD34. Bone marrow biopsy showed hypercellularity with extensive infiltrate of atypical promyelocytes and diminished normal hematopoiesis (Figure 1A). Conventional cytogenetics and fluorescent in situ hybridization (FISH) analysis demonstrated the presence of PML-RARA rearrangement resulting from t(15;17)(q22;q12) translocation. No additional cytogenetic abnormalities were detected. The final diagnosis was t-APL. Given his underlying cardiac condition, the patient was not considered a good candidate for anthracycline-based chemotherapy. He therefore received initial induction therapy with all trans retinoic acid (ATRA) and one dose of gemtuzumab ozogamicin (GO) on day 7 due to hyperleukocytosis secondary to ATRA-induced differentiation. Arsenic trioxide (ATO) was started on day 10. Bone marrow biopsy after hematologic recovery revealed a complete morphologic, cytogenetic and molecular remission. He received consolidation therapy with ATRA and ATO and remained in complete remission for four years. In early 2014, he was found to have moderate thrombocytopenia (platelets, 82 10/L) at a routine follow up. Bone marrow aspirate showed 18% blasts accompanied by trilineage dysplasia. Flow cytometric analysis identified a blast population positive for CD34, CD33, CD13, CD117 (partial), CD15 (partial), CD4, CD7, CD56 (partial), CD41, CD61, and negative for HLA-DR, CD11b, and CD16. Bone marrow biopsy showed hypercellularity with increased interstitial immature cells (less than 20% CD34 positive cells) and many dysplastic megakaryocytes. Conventional cytogenetics revealed a complex karyotype with two related clones: 45,XY,4,del(5)(q13q33),-7,add(19)(q13.4),add(21)(q22)[3]/46,XY, del(X)(q22),t(3;3)(p26;q21),del(5)(q13q33), add(19)(p13)[3]/46,XY[14]. The findings met the diagnostic criteria for refractory anemia with excess blasts2 (RAEB-2). After he was treated with decitabine (four cycles of 10 days each), bone marrow examination revealed complete cytogenetic remission. He then received two cycles of decitabine maintenance of 5 days each. Unfortunately, he again became pancytopenic after a 6 month disease-free period.