Hyo S. Han

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors

IntroductionTrastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.MethodsPatients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.ResultsA total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.ConclusionsResults suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.Trial registrationClinicalTrials.gov; identifier: NCT00963547.

A phase I study of indoximod in patients with advanced malignancies

Purpose Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. Experimental Design Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. Results In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (∼12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. Conclusions Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

Racial differences in acute toxicities of neoadjuvant or adjuvant chemotherapy in patients with early-stage breast cancer

BACKGROUND Racial disparities in breast cancer outcomes are attributed to differences in baseline tumour characteristics and biology, stage, age, ethnic background and socioeconomic factors. However, little is known about racial differences in treatment-related toxicities. We hypothesised that racial/ethnic differences result in differential tolerance to chemotherapy potentially, leading to compromised dose intensity/density of chemotherapy in patients with early-stage breast cancer. METHODS Data were collected from patients treated at five international centers for early breast cancer with the same adjuvant/neoadjuvant chemotherapy (FEC 100: fluorouracil 500mg/m(2), epirubicin 100mg/m(2), and cyclophosphamide 500mg/m(2),every 21d for 3-6 cycles). Toxicities were assessed by first episode of ⩾grade 2 toxicity. RESULTS Toxicities were compared according to four race/ethnicity groups (103 Caucasian, 30 African American, 164 Asian, and 34 Hispanic patients). Tumour characteristics across four race/ethnicity groups were similar. Asians had a significantly higher rate of grade 3 haematologic toxicity than Caucasians, African Americans or Hispanic women (32%, 16%, 10%, and 15%, respectively; p<0.05). In multivariate analysis, only lower BMI was associated with a higher incidence of ⩾grade 3 toxicities. However, no significant differences in chemotherapy dose intensity/density were shown across the four race/ethnicity groups. CONCLUSION Racial differences in acute toxicity were noted in women with breast cancer who were treated with FEC 100 chemotherapy, suggesting that extrapolating toxicities from chemotherapy across ethnicities is not possible and emphasising the need to validate safety of chemotherapeutic regimens in patients of different ethnicities by enhancing the participation of minorities in clinical trials.

Regulation of mitosis and taxane response by Daxx and Rassf1

Current theories suggest that mitotic checkpoint proteins are essential for proper cellular response to taxanes, a widely used family of chemotherapeutic compounds. We recently showed that absence or depletion of protein Daxx increases cellular taxol (paclitaxel) resistance—a common trait of patients diagnosed with several malignancies, including breast cancer. Further investigation of Daxx-mediated taxol response revealed that Daxx is important for the proper timing of mitosis progression and cyclin B stability. Daxx interacts with mitotic checkpoint protein RAS-association domain family protein 1 (Rassf1) and partially colocalizes with this protein during mitosis. Rassf1/Daxx depletion or expression of Daxx-binding domain of Rassf1 elevates cyclin B stability and increases taxol resistance in cells and mouse xenograft models. In breast cancer patients, we observed the inverse correlation between Daxx and clinical response to taxane-based chemotherapy. These data suggest that Daxx and Rassf1 define a mitotic stress checkpoint that enables cells to exit mitosis as micronucleated cells (and eventually die) when encountered with specific mitotic stress stimuli, including taxol. Surprisingly, depletion of Daxx or Rassf1 does not change the activity of E3 ubiquitin ligase anaphase promotion complex/C in in vitro settings, suggesting the necessity of mitotic cellular environment for proper activation of this checkpoint. Daxx and Rassf1 may become useful predictive markers for the proper selection of patients for taxane chemotherapy.

Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review

PurposeTriple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC.ResultsAs with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials.ConclusionsThe development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.

Abstract S2-05: Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA+ per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2-mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Citation Format: Han HS, Dieras V, Robson ME, Palacova M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-05.

Abstract P2-15-04: A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo. Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1 st stage, 25 in 2 nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, 5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity. Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, ≥ 2 cycles of chemotherapy after immunotherapy demonstrated 1 PR, 3 PD, 1 pending scan. For the entire phase 1/2 breast cohort (21 in phase 1, 9 in phase 2) the median TTP = 9.85 weeks (3.8-22.1), OS=38.7 (3.8-122.1) weeks, with 1 patient from the phase 1 cohort alive as of June 2014. Ten out of 21 evaluable patients (1 CR, 7 PR, 2 SD, 11 PD) had clinical benefit from chemotherapy after immunotherapy (9 patients had rapid decline and did not get one full cycle of therapy). All but one of the responders had seen prior chemotherapy in the metastatic setting (including a CR after 4 prior lines of chemo). Median OS in the chemo responders was 69.4 wks (30.1-122.1). Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients. Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.

A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer

Background Indoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted. Materials and Methods The phase-1 study combined 7 indoximod dose levels with < 6 Ad.p53-DC vaccinations every 2 weeks. Primary endpoints were maximum-tolerated dose in phase 1 and objective response in phase 2. Flow cytometry measured immune responses. Results Thirty-nine patients were treated. In combination with Ad.p53-DC vaccine, the maximum-tolerated dose of indoximod was 1600 mg twice daily. Attributable toxicities were grade 1–2. Best response was stable disease in 4 patients. Immunologic responses were detected in 7 out of 23 evaluable patients. Median progression-free survival was 13.3 weeks (95% confidence interval, 12.97–21.85) and median overall survival was 20.71 weeks (95% confidence interval, 25.75–46.15). Nine out of 22 patients (40%) benefitted from chemotherapy after vaccination. Median overall survival in chemotherapy responders was 69.4 weeks (30.1–122.1). Conclusions Indoximod 1600 mg twice daily with Ad.p53-DC was well tolerated. There may have been a chemosensitization effect. Future trials should explore combining this treatment with chemotherapy.

Translational genomic research: the role of genetic polymorphisms in MBSR program among breast cancer survivors (MBSR[BC])

Genetic variations of breast cancer survivors (BCS) may contribute to level of residual symptoms, such as depression, stress, fatigue, and cognitive impairment. The objective of this study was to investigate whether particular single-nucleotide polymorphisms (SNPs) moderated symptom improvement resulting from the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program. An overarching goal of personalized medicine is to identify individuals as risk for disease and tailor interventions based on genetic profiles of patients with diseases including cancer. BCS were recruited from Moffitt Cancer Center and University of South Floridas Breast Health Program and were randomized to either the 6-week MBSR(BC) program (n = 92) or Usual Care (n = 93). Measures of symptoms, demographic, and clinical history data were attained at baseline, 6 weeks, and 12 weeks. A total of 10 SNPs from eight genes known to be related to these symptoms were studied using genomic DNA extracted from blood. Our results were examined for effect sizes, consistency, and statistical significance (p < .05). Three SNPs (rs4680 in COMT, rs6314 in HTR2A, and rs429358 in APOE) emerged as having the strongest (though relatively weak) and most consistent effects in moderating the impact of the MBSR program on symptom outcomes. Although effects were generally weak, with only one effect withstanding multiple comparisons correction for statistical significance, this translational behavioral research may help start the identification of genetic profiles that moderate the impact of MBSR(BC). The ultimate goal of this study is the development of personalized treatment programs tailored to the genetic profile of each patient.

Abstract P4-22-23: Phase II trial of selinexor for metastatic triple negative breast cancer

Background: XPO1 (also known as CRM1) is the exclusive nuclear exporter of multiple tumor suppressor proteins (TSP) including p53, p21, BRCA1/2, pRB, FOXO. XPO1 inhibition forces nuclear accumulation of TSPs, thus inducing apoptosis in cancer cells. Selective Inhibitors of Nuclear Export (SINE) compounds are novel, small molecule, slowly reversible inhibitors of XPO1. SINE compounds showed potent cytotoxicity in the majority of TNBC cell lines in vitro and xenografts. Methods: Eligible patients had measurable metastatic TNBC, received at least one prior line of chemotherapy in the setting of metastatic disease (including anthracycline and taxane), and had an ECOG PS 0-1. Selinexor was given at 60 mg orally twice weekly (day 1& 3 of each week), three of each four-week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR, defined as complete response + partial response + stable disease (SD) ≥12 weeks) from Selinexor in patients with TNBC. This study used a Simon two-stage design (null hypothesis CBR 5%, alternate hypothesis CBR 20%) Results: Ten patients with a median age of 60 years (range 44-71) were enrolled between 7/2015 and 1/2016. The median number of prior chemotherapy lines was 2 (range 1-5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and 7 had progressive disease. The median duration of SD was 84 days (range 17-130 days) and all patients experienced progressive disease with a median PFS of 38 days (range 17-130 days). Based on these results, the error probability of observing no response among the first 10 patients is 0.107 under the alternative hypothesis, i.e., P of response =20%, using the Exact binomial test. This false negative error rate is under the planned type II error 0.20, which is consistent with the predefined stopping rule of the study: the study would be halted if no patient achieved objective response (complete or partial response) in the first 10 eligible patients (stage I). The most frequent grade 1 and 2 observed adverse events that were possibly related to Selinexor were nausea 30% (all grade 1), vomiting 50% (40% grade 1), constipation 50% (40% grade 1, 10% grade 2), diarrhea 20%, anorexia 30%, thrombocytopenia 30%, blurred vision 30%. No grade 4 toxicity was noted. Grade 3 toxicity included reversible encephalopathy (10%), irritability (10%), and thrombocytopenia (10%). Conclusion: Selinexor was well tolerated in patients with advanced TNBC but did not result in objective responses in this patient population. Further combination studies can be explored. Citation Format: Han HS, Ismail-Khan R, Carney D, Extermann M, Hogue D, Soliman H, Loftus L, Lee JK, Sullivan D. Phase II trial of selinexor for metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-23.