Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies.

We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1-2.3] vs. 3.5 months [95% CI, 1.7-5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8-9.8] vs. 12.7 months [95% CI, 7.1-18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.

Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer.

KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer.

PURPOSE: Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations. RESULTS: Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index <30 kg/m2, and the absence of lung metastasis was established and validated. Phase I cancer patients in the low-risk group had a median OS of 16.6 months compared with 5.4 months in the high-risk group (p < 0.001). Untreated patients in the low-risk group had a median OS of 6.7 months compared with 3.6 months in the high-risk group (p = 0.033). EXPERIMENTAL DESIGN: We analyzed 163 consecutive patients with advanced KRAS+/TP53+ mutant cancer who were referred to phase I clinical trials, to identify molecular aberrations, clinical characteristics, survivals, and potentially effective treatment regimens. CONCLUSIONS: This study provided preliminary evidence that besides modulation of the proinflammatory state, antiangiogensis and concomitant gene aberration-related therapies may improve the treatment of KRAS+/TP53+ mutant cancer.

Survival of patients with metastatic leiomyosarcoma: the MD Anderson Clinical Center for targeted therapy experience.

Advanced stage leiomyosarcoma (LMS) is incurable with current systemic antitumor therapies. Therefore, there is clinical interest in exploring novel therapeutic regimens to treat LMS. We reviewed the medical records of 75 consecutive patients with histologically confirmed metastatic LMS, who had been referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. To lay the foundation for potential phase I trials for the treatment of advanced LMS, we analyzed tumor response and survival outcome data. The frequent hotspot gene aberrations that we observed were the TP53 mutation (65%) and RB1 loss/mutation (45%) detected by Sequenom or next-generation sequencing. Among patients treated with gene aberration-related phase I trial therapy, the median progression-free survival was 5.8 months and the median overall survival was 15.9 months, significantly better than in patients without therapy (1.9 months, P = 0.001; and 8.7 months, P = 0.013, respectively). Independent risk factors that predicted shorter overall survival included hemoglobin <10 g/dL, body mass index <30 kg/m2 , serum albumin <3.5 g/dL, and neutrophil above upper limit of normal. The median survivals were 19.9, 7.6, and 0.9 months for patients with 0, 1 or 2, and ≥3 of the above risk factors, respectively (P < 0.001). A prognostic scoring system that included four independent risk factors might predict survival in patients with metastatic LMS who were treated in a phase I trial. Gene aberration-related therapies led to significantly better clinical benefits, supporting that further exploration with novel mechanism-driven therapeutic regimens is warranted.

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies.

PURPOSE: Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells--G1, S, and G2/M. METHODS: Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen. RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9). CONCLUSION: Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.

Characteristics and outcomes for patients with advanced vaginal or vulvar cancer referred to a phase I clinical trials program: the MD Anderson cancer center experience.

BACKGROUND: Early-stage vaginal and vulvar cancer can be cured. But outcomes of patients with metastatic disease are poor. Thus, new therapeutic strategies are urgently required. METHODS: In this retrospective study, we analyzed the clinical outcomes of consecutive patients with metastatic vaginal or vulvar cancer who were referred to a phase I trial clinic between January 2006 and December 2013. Demographic and clinical data were obtained from patients' electronic medical records. RESULTS: Patients with metastatic vaginal (n = 16) and vulvar (n = 20) cancer who were referred for phase I trial therapy had median overall survival durations of 6.2 and 4.6 months, respectively. Among those who underwent therapy (n = 27), one experienced a partial response and three experienced stable disease for at least 6 months. Patients with a body mass index ≥30 had a significantly longer median overall survival duration than did those with a body mass index <30 (13.2 months versus 4.4 months, p = 0.04). Preliminary data revealed differences in molecular profiling between patients with advanced vaginal cancer and those with advanced vaginal cancer. CONCLUSIONS: Metastatic vaginal and vulvar cancers remain to be difficult-to-treat diseases with poor clinical outcomes. The currently available phase I trial agents provided little meaningful clinical benefits. Understanding these tumors' molecular mechanisms may allow us to develop more effective therapeutic strategies than are currently available regimens.