A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone.

LESSONS LEARNED: Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. BACKGROUND: We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. METHODS: This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design. RESULTS: Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. CONCLUSION: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

Neratinib-Plus-Cetuximab in Quadruple-WT (KRAS, NRAS, BRAF, PIK3CA) Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study.

PURPOSE: In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment. PATIENTS AND METHODS: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies. RESULTS: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples. CONCLUSIONS: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

Pancreatic Cancer in Lynch Syndrome: A Case Report.

Background: In the literature, pancreatic cancer is not frequently acknowledged among the tumors that are considered a part of Lynch Syndrome. Case Presentation: Our case is one of a young man who was found, very early in life, to have pancreatic cancer. His tumor demonstrated germline microsatellite instability, and hence by definition the patient has Lynch syndrome. He responded well to treatment, which included surgery and adjuvant chemotherapy. To date he remains in remission from pancreatic cancer. Conclusion: The rare instances in this case report include: (a) The patient had pancreatic cancer that fulfilled the histopathological and clinical criteria for Lynch syndrome. (b) Pancreatic cancer was diagnosed earlier in our patient than is expected in patients who suffer from pancreatic cancer as a part of Lynch syndrome. (c) Our patient had an excellent response to chemotherapy. He remains in remission to date from pancreatic cancer and is 5 years since his last treatment for this disease.

HER-2-Positive Ampullary Adenocarcinoma: A Case Report.

Background: Ampullary adenocarcinomas are a rare subset of periampullary tumors with an overall poor prognosis. Treatment decisions are generally extrapolated from pancreatic chemotherapy protocols and consist mainly of traditional chemotherapy drugs. There are no known targets for therapeutic intervention in ampullary adenocarcinoma at this time. Next generation sequencing and other novel molecular profiling of tumors, including circulating tumor DNA (ctDNA), have recently made it possible to better understand tumor biology and elucidate driver mutations which are amenable to targeted therapy. This case describes the use of novel DNA sequencing technology to provide a targeted treatment option, HER-2 inhibition, in a patient with HER-2 overexpressing ampullary adenocarcinoma. This is the first time this has been described in the literature. Case presentation: The patient is a 63-year-old Caucasian man who initially presented with symptoms of obstructive jaundice and was found to have a periampullary tumor. He underwent resection of his tumor and pathology confirmed a stage IIB ampullary adenocarcinoma. He unfortunately developed a recurrence in the liver and lung two years later. Next generation sequencing of his tumor at the time of resection as well as ctDNA analysis demonstrated a HER-2 overexpressing tumor. Following first line therapy with FOLFOX he had progression and was treated with trastuzumab and pertuzumab with stabilization of his disease prior to his ultimate demise from multifocal pneumonia. Conclusion: The use of next generation sequencing as well as ctDNA technology generated a novel therapeutic intervention in our patient. As these techniques become more widespread, it is likely more targeted therapies will be used in these difficult to treat diseases.

Hepatoid Carcinoma of the Pancreas: A Case Report and Review of the Literature.

Background: Hepatoid carcinoma (HC) is a rare extrahepatic malignancy that shares many morphological and serological features with hepatocellular carcinoma. HC has been reported to arise from several organs that are derived from the foregut endoderm, including the stomach, gallbladder, and pancreas. We present a case of an elderly man with hepatoid adenocarcinoma of the pancreatic head with duodenal invasion, presenting with pancreatitis and a gastrointestinal bleed. With only 23 reported cases at the time of our literature search, we discuss the presentation, histopathology, and management of such a rare disease. Case presentation: A 71-year-old man presented initially with abdominal pain and was treated conservatively for pancreatitis. Four months later, he presented with melena and anemia. His examination was noncontributory. Esophagogastroduodenoscopy revealed a friable ampulla of Vater, and a CT scan of the abdomen showed a 4.5 cm pancreatic head mass. Fine needle aspirate revealed an epithelioid neoplasm with hepatoid morphology. Serum α-fetoprotein was normal. Surgical resection confirmed hepatoid adenocarcinoma of the pancreas with positive lymphadenopathy and negative margins. There was no radiographical or gross evidence of distant spread. Observation and adjuvant gemcitabine were discussed as possible options. The patient elected to receive care closer to home and will continue surveillance imaging. Conclusion: With only 23 reported cases, pancreatic HC represents a rare entity within gastrointestinal oncology. There is no clear postoperative adjuvant standard therapy for this likely heterogeneous group of tumors. Although surgical resection is the mainstay of upfront treatment, metastatic disease to the lymph nodes or liver portends a poor prognosis and may warrant treatment such as transarterial embolization, chemotherapy, or radiotherapy.

Refractory fallopian tube carcinoma - current perspectives in pathogenesis and management.

Fallopian tube carcinoma (FTC) is considered a rare malignancy, but recent evidence shows that its incidence may have been underestimated. Risk-reducing salpingo-oophorectomy (RRSO) in breast cancer susceptibility gene (BRCA)-positive women has provided a unique opportunity to study the pathogenesis of FTC and ovarian carcinomas. Newer data now suggest that most high-grade serous cancers of the ovary originate in the fimbrial end of the fallopian tube. Due to the presumed rarity of FTC, most current and more recent ovarian cancer clinical trials have now included patients with FTC. The treatment guidelines recommend similar overall management and that the same chemotherapy regimens be used for epithelial ovarian cancers and FTC.

A case of periampullary adenocarcinoma in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder with a known predisposition to gastrointestinal neoplasms such as stromal tumors and carcinoids. Adenocarcinomas (ACs) of the gastrointestinal tract are relatively rare in patients with NF-1, especially those found in the periampullary region. We present a case report of periampullary adenocarcinoma in a 56-year-old woman with NF-1 who presented with abdominal pain and obstructive jaundice.