A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. METHODS: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. CLINICAL TRIAL: gov identifier: NCT04089553.

First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

PURPOSE: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. RESULTS: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. CONCLUSIONS: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Cytochrome P450 3A4FNx011B as pharmacogenomic predictor of tacrolimus pharmacokinetics and clinical outcome in the liver transplant recipients.

BACKGROUND AND AIMS: Tacrolimus is a macrolide immunosuppressant used for prevention of allograft rejection in organ transplantation and metabolized in the liver and intestine by cytochrome P450 3A4 (CYP3A4) enzyme. A single nucleotide polymorphism (SNP) in the CYP3A4 promoter region has been identified. It has been shown that the presence of CYP3A4FNx011B allele (variant GG) is associated with a reduced catalytic activity of CYP3A4 in vivo. The aim of this study was to determine the role of CYP3A4FNx011B on tacrolimus dosing and clinical outcome in liver transplant recipients. SUBJECTS AND METHODS: Forty-eight liver transplant recipients were stratified according to the genotype. There were 32 wild-type (AA) patients and 5 homozygous variant (GG) and 11 (AG) heterozygous. Tacrolimus doses and trough concentrations as well as phenotypic data were collected in the first 10 days of the transplant. RESULTS: The tacrolimus concentration was significantly higher in the wild (AA) group as compared to homozygous variant (GG) and heterozygous (AG) patients. Homozygous variant (GG) group had significantly lower dose requirements. However, no significant difference was observed in the concentration/dose ratio between all groups. CONCLUSIONS: Based on our results, it may be concluded that CYP3A4FNx011B of recipient is an important factor influencing pharmacokinetic of tacrolimus, as patients with CYP3A4FNx011B polymorphism may require lower tacrolimus doses to maintain therapeutic levels. The dose reduction may not affect clinical outcomes after liver transplant.

Altered cytochrome p450 metabolism of calcineurin inhibitors: case report and review of the literature.

A 19-year-old woman was admitted to receive a kidney transplant from a nonliving donor. At the time of transplantation, she was taking oral phenytoin 300 mg every morning, 100 mg at noon, and 300 mg every evening (total of 700 mg/day) to treat seizures secondary to hemodialysis. Immediately after the transplantation, phenytoin treatment was resumed, and immunosuppressive therapy consisting of antithymocyte globulin, cyclosporine, mycophenolate mofetil, and corticosteroids was started. Her cyclosporine blood levels varied over the first 10 days after transplantation. Cyclosporine was discontinued, and tacrolimus was begun after acute rejection was discovered. The rejection was treated with antithymocyte globulin, plasmapheresis, and intravenous immunoglobulin, and subsequently resolved; however, the patient's blood concentrations of tacrolimus varied widely. Phenytoin is an antiepileptic drug that induces hepatic enzymes, affecting the cytochrome P450 3A family. These enzymes metabolize approximately 50% of all prescribed drugs, including cyclosporine and tacrolimus. According to the Naranjo adverse drug reaction probability scale, this patient's adverse drug reaction probably occurred from altered metabolism of cyclosporine and tacrolimus due to phenytoin therapy. Clinicians must identify drug interactions between metabolic enzyme inducers or inhibitors and drug substrates with narrow therapeutic ranges, closely monitor drug concentrations, and observe patients for clinical signs and symptoms of therapeutic failure or toxicity. In daily practice, clinicians should explore the metabolic characteristics of drugs and their biotransformation pathways to identify patients who require alternative therapy.

Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation.

It has been almost 50 years since the first child was born to a female transplant recipient. Since that time pregnancy has become common after transplantation, but physicians have been left to rely on case reports, small series and data from voluntary registries to guide the care of their patients. Many uncertainties exist including the risks that pregnancy presents to the graft, the patient herself, and the long-term risks to the fetus. It is also unclear how to best modify immunosuppressive agents or treat rejection during pregnancy, especially in light of newer agents available where pregnancy safety has not been established. To begin to address uncertainties and define clinical practice guidelines for the transplant physician and obstetrical caregivers, a consensus conference was held in Bethesda, Md. The conferees summarized both what is known and important gaps in our knowledge. They also identified key areas of agreement, and posed a number of critical questions, the resolution of which is necessary in order to establish evidence-based guidelines. The manuscript summarizes the deliberations and conclusions of the conference as well as specific recommendations based on current knowledge in the field.

Thiopurine S-methyltransferase genotype predicts azathioprine-induced myelotoxicity in kidney transplant recipients.

Azathioprine (AZA) is an immunosuppressive prodrug that undergoes metabolism by thiopurine S-methyltransferase (TPMT). Eighty to ninety-five percent of low or deficient TPMT enzyme activity is genetically determined by the presence of three nonfunctional mutant alleles: TPMT*2, TPMT*3A and TPMT*3C. Using TPMT as a pharmacogenetic paradigm, we explored the association between these genetic mutations and development of adverse drug effects in an ethnically diverse renal transplant population receiving azathioprine. Biochemical and clinical data were retrospectively evaluated during the first four weeks after kidney transplantation. TPMT nonfunctional mutant alleles were identified by polymerase chain reaction-based methods. Of 89 patients initially consented, 36 met inclusion criteria for this retrospective study. Five patients possessing a single TPMT nonfunctional mutant allele were identified: TPMT*3A: n = 2 Caucasians; TPMT*3B: n = 1 Caucasian; TPMT*3C: n = 2 African-Americans. TPMT nonfunctional mutant alleles were associated with significant reductions in hematological indices and a significant increase in cyclosporine plasma concentrations in the first month post-transplant. TPMT genotype was an independent predictor for hemoglobin, hematocrit and red blood cell changes while mean azathioprine dose (mg/kg/day), azathioprine dose (mg/kg/day) at day 30 and cyclosporinemia at day 30 were not. Prospective application of pharmacogenetic principles may assist in optimization of immunosuppressive drug therapy and minimize drug toxicities.

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

BACKGROUND: FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled. RESULTS: FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure. CONCLUSIONS: At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.

Obesity does not portend a bad outcome for kidney transplant recipients.

BACKGROUND: Kidney transplant programs may avoid transplantation in obese patients because of reports indicating that obese patients have poorer outcomes than do nonobese patients. We recently reviewed our experience. METHODS: Patients receiving a kidney transplant between January 1, 1990 and December 31, 1999 were divided according to body mass index (BMI): group 1, BMI<25 (n=457); group 2, BMI> or =25 and <30 (n=278); and group 3, BMI> or =35 (n=98). RESULTS: Cadaveric graft survival rates at 2 years were 85% for group 1, 88% for group 2, and 85% for group 3 (P>0.10). Cadaveric patient survival rates at 2 years were 92% for group 1, 91% for group 2, and 94% for group 3 (P>0.10). There were no differences in technical losses or in posttransplantation wound complications. Group 3 patients, however, did have a higher incidence of steroid-induced posttransplantation diabetes mellitus than the other two groups (P<0.01). CONCLUSION: Obese transplant recipients have similar outcomes to nonobese patients.