Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors

BackgroundPamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors.MethodsOral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed.ResultsAcross stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics.ConclusionsPamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted

Characterization of In Vitro and In Vivo Metabolic Pathways of the Investigational Anticancer Agent, 2-Methoxyestradiol

The aim of this study was to characterize the metabolic pathways of 2-methoxyestradiol (2ME2), an investigational anticancer drug. In vitro metabolism studies were performed by incubation of 2ME2 with human liver microsomes under various conditions and metabolite identification was performed using liquid chromatography-tandem mass spectrometry. In microsomal mixtures, four major oxidative metabolites and two glucuronic acid conjugates were observed originating from 2ME2. Human liver S9 protein fraction was used to screen for in vitro sulfation but no prominent conjugates were observed. The total hepatic clearance as estimated using the well-stirred model was approximately 712 mL/min. In vivo metabolism, assessed using 24-h collections of urine from cancer patients treated with 2ME2 revealed tha

Plasma Protease-Mediated Metabolism of Carfilzomib and Its Implications on Clinical Effects and Side Effects

Abstract Introduction: Similar to most other anti-cancer drugs, carfilzomib is administered at a defined dose per m2. Inspired by preclinical data showing that extrahepatic peptidases play an important role in the metabolism of carfilzomib, using samples from a prospective clinical trial, we conducted an investigation focusing on concentrations of albumin in peripheral blood and its effects on plasma protease-mediated metabolism of carfilzomib. Methods: Baseline laboratory values, pharmacokinetics data, and response data were collected from the clinical trial. Minimal residual disease was determined by multi-parametric flow cytometry utilizing, 8-color flow panel and analyzes ≥ 3 x 106 events (sensitivity 1 x 10-5). To study the rate of metabolism in plasma, apheresis samples were obtained from the NIH blood bank, lyophilized albumin was added to plasma with and without a non-specific protease inhibitor cocktail (1X). Carfilzomib concentrations were obtained at several time points over the course of 24 hours by mass spectrometry via previously published methods. Results: Patients with baseline serum albumin >4.0 g/dL had a near 4-fold greater clearance (1576 L/h vs 401.1 L/h; n=9 vs n=34) that was further increased in patients with normal white blood cell count. Consistent with the increase in clearance, 80% of patients (29/33) with albumin 4.0 g/dL had a similar outcome. Therefore, individuals with baseline albumin >4.0 g/dL are at significantly greater risk for not responding to the combination of carfilzomib, lenalidomide, and dexamethasone [OR (95%CI) = 7.3 (1.4-36.7); P=0.0049]. Median progression-free survival was also longer in patients with albumin 4.0 g/dL (unreached vs. 18.8 months; P=0.0002). A trend between albumin and lymphopenia was also detected (P=0.17). The addition of 1.0 g/dL albumin increased the ex vivo proteolytic rate of carfilzomib in apheresis plasma from healthy individuals (74% vs 57.2% unreacted carfilzomib after 24 hours at 37°C), and the addition of a non-specific protease inhibitor reduced carfilzomib metabolism in plasma Conclusions: Although they have lower grade myeloma, patients with albumin >4.0 g/dL, surprisingly, are at greater risk at having worse clinical outcomes to carfilzomib therapy; this finding appears to depend upon the ability of albumin to directly potentiate plasma protease-mediated metabolism of carfilzomib. Therefore, dose adjustments or concomitant therapy with protease inhibitors may be warranted in such patients. Efforts are underway to identify specific proteases that metabolize carfilzomib and determine potential inhibitors that may be clinically useful. Disclosures No relevant conflicts of interest to declare

CX-2029, a PROBODY drug conjugate targeting CD71 (transferrin receptor): Results from a first-in-human study (PROCLAIM-CX-2029) in patients (Pts) with advanced cancer.

3502 Background: CX-2029 is a PROBODY drug conjugate (PDC) of MMAE, a potent microtubule inhibitor, directed against CD71 (transferrin receptor 1). In addition to being an abundant tumor antigen, CD71 is highly expressed on normal cells, precluding targeting by a traditional antibody drug conjugate (ADC). PDCs are masked ADCs, unmasked predominantly by tumor-associated proteases, thereby restricting target engagement to tumors. Both a CD71 PDC and ADC displayed broad activity in multiple xenograft tumor models; in toxicology studies, the PDC was tolerable at doses consistent with efficacy in non-clinical tumor models while the ADC was not. Methods: In a phase 1/2 first-in-human study of PDC CX-2029 in advanced solid tumors (NCT03543813), pts with ECOG 0–1 and ≥1 prior systemic therapy were enrolled into escalating dose cohorts of the PDC CX-2029 given IV every 21 days. Endpoints included evaluation of MTD, safety, antitumor activity, and potential biomarkers; plasma and tissue samples were collected for PK/PD analyses. Preliminary results are reported. Results: As of 30 November 2019, 34 pts were enrolled (median age 59 y; 59% male; 71% ECOG 1; median [range] of 3 [1–16] prior therapies). Pts received a median of 3 (1–12) CX-2029 doses. Starting dose for escalation was 0.1 mg/kg. Following a single CX-2029 dose, median molar ratio of masked CX-2029 to total CX-2029 for AUCtau was 0.938 (0.864–0.942); the ratio of free MMAE to total CX-2029 was \u3c0.03. Infusion-related reactions were the most common treatment-related AE (TRAE) of any grade (88%; primarily low grade and with first infusion), followed by anemia (56%), fatigue and nausea (24% each), neutropenia (21%), and leukopenia (12%). Grade 3+ TRAEs in ≥10% pts were anemia (35%) and neutropenia (18%). In 32 response-evaluable pts, 1 pt had a confirmed partial response (squamous NSCLC); 9 had stable disease including 1 pt with ocular melanoma treated for 36 weeks. Conclusions: The observed safety profile for CX-2029 effectively reduces on-target toxicity for this previously undruggable target, supporting the PROBODY platform. Evidence of anti-tumor activity was observed. Dose escalation continues. Clinical trial information: NCT03543813

ANG1005, a brain penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases.

PURPOSE: ANG1005, a novel taxane derivative, consists of 3 paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. EXPERIMENTAL DESIGN: A multi-center, open-label phase 2 study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis (LC) was conducted (n=72 BCBM; n=28 LC subset). ANG1005 was administered IV at 600 mg/m RESULTS: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS directed therapies was 2.6 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology review). In the LC subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI 5.4 - 9.4). CONCLUSIONS: Even though the study pre-set rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients, particularly in LC patients, including symptom improvement and prolonged overall survival compared to historical control