KT-253, A Novel MDM2 Degrader and p53 Stabilizer, Has Superior Potency and Efficacy Than MDM2 Small Molecule Inhibitors.

Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors (SMIs) have demonstrated limited activity, underscoring an unmet need for a better approach to target MDM2. KT 253 is a highly potent and selective heterobifunctional degrader that overcomes the MDM2 feedback loop seen with SMIs and induces apoptosis in a range of hematologic and solid tumor lines.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD.

Management of adverse events from the treatment of encorafenib plus cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer: insights from the BEACON CRC study.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC.

Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS).

Background: In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented.

Methods: COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma.

Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study.

Purpose: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with V600E-mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data.

Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.

Background: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.

Methods: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300).

Encorafenib, Binimetinib, and Cetuximab in V600E-Mutated Colorectal Cancer.

Background: Patients with metastatic colorectal cancer with the V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.

Methods: In this open-label, phase 3 trial, we enrolled 665 patients with V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens.

Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management.

Background: Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib.

Patients And Methods: Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily.

Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study.

Purpose: To determine the safety and preliminary efficacy of selective combination targeted therapy for V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).

Patients And Methods: Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab.

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.

Objective: PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib.

Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study.

Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36).

Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.

Treatment options are limited for patients with imatinib-resistant or -intolerant accelerated phase chronic myeloid leukemia (CML-AP). Dasatinib is a novel, potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC-family kinases that showed marked efficacy in a phase 1 trial of patients with imatinib-resistant CML. Results are presented for 107 patients with CML-AP with imatinib-resistance or -intolerance from a phase 2, open-label study further evaluating dasatinib efficacy and safety.

Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases.

Phase I study of a novel taxane BMS-188797 in adult patients with solid malignancies.

Purpose: Preclinical studies show that BMS-188797 has a broad spectrum of antitumor activity in in vitro cytotoxicity assays and tumor xenograft models. We did a phase I trial designed to determine the maximum tolerated dose and the pharmacokinetics of BMS-188797 when administered i.v.

Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies.

Purpose: The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly.

Experimental Design: Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v.

Translational regulation as a novel mechanism for the development of cellular drug resistance.

Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.

Use of paclitaxel in patients with pre-existing cardiomyopathy: a review of our experience.

Cardiac toxicity is frequently the indication for discontinuation of an anthracycline in patients with tumors which remain anthracycline-sensitive. During the 1990s, the most frequently used second-line agents at the Yale Cancer Center (YCC) were the taxanes. The goal of this retrospective analysis was to determine the effect of paclitaxel on cardiac function in patients with cardiomyopathy.

The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function.

Breast cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy. We treated 52 patients with inflammatory and/or metastatic disease with sequential high-dose melphalan and stem cell rescue followed by high-dose thiotepa and stem cell rescue. Stem cells were mobilized with cyclophosphamide and/or paclitaxel and filgrastim.

Peripheral blood progenitor cell cycle kinetics following priming with pIXY321 in patients treated with the "ICE" regimen.

Purpose: Treatment with hematopoietic growth factors increases the percentage of hematopoietic progenitor cells in cell cycle. Following withdrawal of certain growth factors, preclinical data suggest that there is a transient fall in the percentage of progenitor cells in cycle below the baseline, thus providing a window to administer chemotherapy with reduced risk of myelotoxicity.

Patients And Methods: Patients with histologically confirmed, previously untreated neoplasia, were treated with pIXY321 by subcutaneous injection at a dose of 375 microg/m2 twice daily (total dose 750 microg/m2/day) for seven days (days -8 to -2), followed by a two-day rest (days -1 to 0).

p53 mutations do not predict response to paclitaxel/radiation for nonsmall cell lung carcinoma.

Background: Mutations in the tumor suppressor gene p53 have been associated with resistance to ionizing radiation and chemotherapy. Paclitaxel and concurrent radiation (paclitaxel/RT) achieve high response rates with locally advanced nonsmall cell lung carcinoma (NSCLC). In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function.

Management of persistent B19 parvovirus infection in AIDS.

An HIV+ 26-year-old white man with a CD4 count of 0.06 x 10(9)/l was found to have red blood cell aplasia secondary to B19 parvovirus infection. Regular infusions of intravenous immunoglobulin (IVIG) were begun and resulted in marked reticulocytosis and correction of anaemia.