Purpose
The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, ...TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).
Methods
Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.
Results
A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.
Conclusion
The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.
ClinicalTrials.gov Identifier
NCT02353026.
In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; ...durvalumab was noninferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or nonviral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan.
In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per Response Evaluation Criteria in Solid Tumors, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan.
The Asian subgroup included 479 participants randomised to STRIDE (n=156), durvalumab (n=167), or sorafenib (n=156). OS was improved for STRIDE vs. sorafenib (HR 0.68; 95% CI 0.52-0.89). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n=141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%).
STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including the Asia-Pacific region.
NCT03298451
The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS, vs. sorafenib, and that durvalumab monotherapy was noninferior to sorafenib in participants with unresectable hepatocellular carcinoma (uHCC). However, there are differences in the aetiology and clinical practices related to HCC in parts of Asia, compared to Western countries and Japan, which could lead to differences in treatment outcomes between these regions. The results of this analysis demonstrate the benefits of STRIDE for participants in the Asia-Pacific region, consistent with the full, global study population. Overall, these findings continue to support the use of STRIDE in a diverse population, reflective of uHCC globally.
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•The HIMALAYA study showed improved outcomes with STRIDE vs. sorafenib in unresectable hepatocellular carcinoma (uHCC).•In an Asian subgroup of HIMALAYA, STRIDE improved overall survival and objective response rates vs. sorafenib.•Outcomes were improved with STRIDE vs. sorafenib in the subgroup of participants enrolled in Hong Kong and Taiwan.•Treatment-related adverse events with STRIDE were generally manageable and low grade in the Asian subgroup.•STRIDE is beneficial for people with uHCC in the Asia-Pacific region, consistent with the global study population.
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. It arises from modulation of multiple genes by mutations, epigenetic regulation, noncoding RNAs and ...translational modifications of encoded proteins. Although >40% of HCCs are clonal and thought to arise from cancer stem cells (CSCs), the precise identification and mechanisms of CSC formation remain poorly understood. A functional role of transforming growth factor (TGF)-β signalling in liver and intestinal stem cell niches has been demonstrated through mouse genetics. These studies demonstrate that loss of TGF-β signalling yields a phenotype similar to a human CSC disorder, Beckwith-Wiedemann syndrome. Insights into this powerful pathway will be vital for developing new therapeutics in cancer. Current clinical approaches are aimed at establishing novel cancer drugs that target activated pathways when the TGF-β tumour suppressor pathway is lost, and TGF-β itself could potentially be targeted in metastases. Studies delineating key functional pathways in HCC and CSC formation could be important in preventing this disease and could lead to simple treatment strategies; for example, use of vitamin D might be effective when the TGF-β pathway is lost or when wnt signalling is activated.
Purpose
For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored ...whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response.
Methods
We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan–Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis.
Results
For all patients, median overall survival (mOS) was 13 months (95% CI 8–19), and median progression-free survival (mPFS) was 6 months (95% CI 4–10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s),
p
< 0.0001) and mOS (not met vs. 11 vs. 3 months,
p
< 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months
p
= 0.133) and mOS (17 vs. 9 months;
p
= 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months,
p
= 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (
p
= 0.0043).
Conclusion
We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.
Purpose
Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with ...paclitaxel in patients with advanced or metastatic solid tumors.
Methods
Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.
Results
Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1–4, 8–11, 15–18, and 22–25, and 100 mg/m
2
paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7–28 weeks).
Conclusions
This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.
The role of radiation therapy in the management of unresectable pancreatic cancer is controversial. One concern about concurrent chemoradiation relates to the timing of chemotherapy. In contrast to ...conventional radiation therapy, stereotactic body radiation therapy (SBRT) delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here, we report our results of patients treated with SBRT and chemotherapy for inoperable pancreatic cancer.
Thirty-eight patients treated with SBRT and chemotherapy for locally advanced, borderline resectable, and medically inoperable pancreatic cancer at our institution from January 2008 to December 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction over 5 days. Toxicities were scored using the Common Terminology Criteria for Adverse Events version 3. Survival was calculated using the Kaplan-Meier method.
The median age was 70 years (range, 45 to 90 y). Eastern Cooperative Oncology Group performance status ranged from 0 to 3. Thirty-four patients received concurrent chemotherapy. Four patients received sequential chemotherapy. Median overall survival was 14.3 months and median progression-free survival was 9.2 months from diagnosis. From radiation, overall survival and progression-free survival were 12.3 and 6.8 months, respectively. The overall local control rate was 79%. Acute toxicity was minimal. Severe late SBRT-related toxicities included 1 grade 3 gastric outlet obstruction, 1 grade 4 biliary stricture, and 1 grade 5 gastric hemorrhage.
SBRT combined with chemotherapy for unresectable pancreatic cancer is convenient, feasible, and generally well tolerated. Outcomes of SBRT combined with chemotherapy compare favorably to results obtained with chemotherapy and conventional radiation therapy.
Purpose
We report our institutional observations of ten patients with advanced hepatocellular carcinoma (HCC) (seven and three were Child–Pugh class A and B, respectively) who received compassionate ...regorafenib therapy between June 2016 and January 2017. These patients did not fit the rigid criteria of a clinical trial and represented the use of regorafenib in an everyday clinic situation.
Methods
Regorafenib (160 mg P.O. daily) was administered to patients on a 4-week cycle (3 weeks on, 1 week off) until disease progression (assessed using mRECIST criteria) or discontinuation secondary to toxicity (assessed using CTCAE criteria). Relevant clinical data were abstracted from patient medical records and reviewed retrospectively.
Results
The median duration of patient treatment was 6.6 weeks, and the median time to disease progression was 12.5 weeks. Most common treatment emergent adverse events were fatigue, diarrhea, and hand–foot skin reaction. Elevated AST and ALT were the most commonly observed laboratory-assessed adverse events, which reached grade 3 status in the Child–Pugh class B patients only. We observed intolerance to regorafenib treatment in one patient who had previously received a liver transplant. We also saw lithium toxicity in one patient receiving long-term lithium treatment, suggesting a potential and unexpected drug–drug interaction with regorafenib.
Conclusions
Taken together, our observations indicate that regorafenib is beneficial in the treatment of patients with advanced HCC who progressed on or demonstrated intolerance to sorafenib therapy; however, careful selection and close monitoring of patients is necessary to maximize the benefit while minimizing the toxicities of regorafenib treatment.
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