Purpose
Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A ...(capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.
Methods
A modified ‘3 + 3’ dose-escalation design was employed. Patients received pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy.
Results
Eighteen patients were enrolled: Six patients received pilaralisib 400 mg QD and 12 patients received pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response.
Conclusions
With pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of pilaralisib.
The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic ...drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (
values from 6 × 10
to 3 × 10
). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (
= 4.6 × 10
, 6.5 × 10
, and 3.4 × 10
, respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85;
= 1.3 × 10
) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (
= 6.8 × 10
and 7.8 × 10
for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.
To evaluate the role of postchemotherapy adjunctive surgery in patients with liver metastases from germ cell cancer (GCT).
Forty-three male patients with nonseminoma were treated in different ...multicenter treatment protocols between 1990 and 1999, and they underwent hepatic surgery. The results of postchemotherapy surgical resection, histologic findings found during postchemotherapy surgery, and prognostic factors for survival were assessed.
Thirty-five of 43 patients (81%) were initially diagnosed with liver metastases and advanced GCT, and 8 patients (19%) presented with metachronous liver metastases after a median interval of 16 months (range, 6-103 months). Twelve patients (28%) had isolated liver metastases after completion of chemotherapy, while 31 patients (72%) had additional residual extrahepatic tumor masses. Liver surgery included tumor excision or segmentectomy in 32 patients (74%) and hepatectomy (right/left) or resection of multiple segments in 11 patients (26%). Histologic analysis of postchemotherapy resected residua yielded necrosis in 67%, teratoma in 12%, and viable cancer in 21%. Additional resections at other sites have been performed in 31 patients revealing necrosis in 61% (n = 19), teratoma in 29% (n = 9), and vital carcinoma in 10% (n = 3). In 39% of patients, histologic findings differed among liver and other resection sites. Refractoriness to chemotherapy was associated with a shorter survival after surgery, and a trend was seen in patients with elevation of AFP.
The high rate of viable cancer and teratoma found in liver specimens, differing histologic results at residual tumor locations, and the high survival rate achieved support a multidisciplinary approach including resection of liver masses since no accurate selection of patients can narrow the use of surgery.
Testicular cancer has a favorable prognosis in the majority of patients due to the excellent susceptibility to chemotherapy with cisplatin, etoposide and bleomycin (BEP), which is commonly ...administered over 3-4 cycles of treatment.
A 22-year-old male failed to achieve complete response after unconventional treatment with 6 courses of BEP for intermediate-risk metastasized testicular cancer. The patient developed chemotherapy-induced digital necrosis and substantial loss of digital function after this excessive treatment. This condition resolved with infusional alprostadil combined with oral clonidin and pentoxifyllin.
Infusional alprostadil adds substantial clinical benefit to combined vasoactive therapy in chemotherapy-induced vascular toxicity, even after the onset of digital necrosis.
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