Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study.

PURPOSE: Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. PATIENTS AND METHODS: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. RESULTS: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (P = 0.01) indicative of clinical outcome. CONCLUSIONS: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.

A feasibility study of virtual group therapy to improve quality of life of cancer caregivers.

BACKGROUND: Cancer caregiving can negatively impact the quality of life (QOL) of the caregiver. In-person interventions for improving coping skills have been shown to be effective in improving QOL for caregivers. OBJECTIVES: This pilot project explored the feasibility and acceptability of a virtual group therapy intervention to improve short-term cancer caregiver QOL. METHODS: Caregivers of cancer patients were enrolled in a structured multidisciplinary intervention of eight virtual group therapy sessions provided over four weeks between September 9, 2013 and November 17, 2014. Group sessions were led by trained facilitators and included components of physical therapy, occupational therapy, psychosocial education, cognitive-behavioral intervention, supportive discussion, spiritual reflection, and mindfulness therapy. Feasibility was based on acceptable number of recruited participants per session; acceptability was defined using attendance and 80% QOL completion rates. QOL domains and symptom burden were assessed using validated single items. RESULTS: The 20 cancer caregivers who enrolled were mostly older (80% were ≥ 65 years), female (76.5%), married to the patient (88.2%), Caucasian (100%), and highly educated (100%). 60% attended one to five sessions, 15% attended six to eight sessions, and 25% attended no sessions. Thirty percent completed pre- and post- intervention ratings of QOL items. SIGNIFICANCE OF RESULTS: Findings suggested that a virtual group therapy intervention is feasible for the cancer caregivers in this study. Although not statistically significant, the caregivers reported higher QOL and less symptom burden in multiple domains after participating in the virtual group therapy intervention.

Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group Trial N0745 (Alliance).

BACKGROUND: Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis. OBJECTIVE: To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC. PATIENTS AND METHODS: Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID. RESULTS: Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively. CONCLUSIONS: The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.).

Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147.

BACKGROUND: KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. METHODS: Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. RESULTS: KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF (V600E) mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF (V600E) mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. CONCLUSIONS: Specific patient and tumor characteristics are associated with KRAS and BRAF (V600E) mutations.