Din 6924 Vs Din 985

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We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype (TP53-WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles. Intracellular proteolysis of ALRN-6924 forms a long-acting active metabolite with potent MDM2 and MDMX binding affinity and slow dissociation kinetics. At high doses, ALRN-6924 exhibits on-mechanism anticancer activity in TP53-WT tumor models. At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent.

Patients and methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days.

Results: Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.

Current address for M.N. Saleh: The Aga Khan University Hospital, Nairobi, Kenya; current address for J.R. Infante: Janssen Pharmaceuticals, Horsham, Pennsylvania; and current address for G. Rabinowits: Miami Cancer Institute, Miami, Florida.

Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days.

On the basis of low central nervous system penetration of ALRN-6924 prototypes observed in preclinical studies, patients with primary central nervous system tumors and patients with known brain metastasis were excluded unless these metastases had been treated and been clinically stable for at least 30 days. Patients with cardiovascular risk factors, including the New York Heart Association class III or IV heart failure, uncontrolled arrythmias or hypertension, and acute coronary syndromes within 6 months, as well as patients with active or uncontrolled infections, including HIV/AIDS and hepatitis B and C, were excluded. Any previous primary malignancy must have been in remission for at least 2 years, except for non-melanoma skin cancers, carcinomas in situ, or squamous intraepithelial neoplasms. Patients with pulmonary embolism, deep venous thrombosis, gastrointestinal hemorrhage in the past 6 months, hereditary angioedema of any severity, or history of severe or life-threatening angioedema due to any cause were also excluded. Finally, use of concomitant medications that are predominantly cleared by organic anion transporter polypeptide (OATP) hepatobiliary transporters OATP1B1 and OATP1B3 was prohibited within 48 hours of ALRN-6924 infusion because ALRN-6924 is primarily cleared through hepatobiliary elimination and inhibits these transporters.

Before patient recruitment began at each participating site, the protocol was approved by its institutional review board. All patients provided written informed consent before undergoing study-related procedures, including the molecular assessment of tumor specimens. This trial was conducted in accordance with current United States FDA regulations, ICH Good Clinical Practice Guidelines, the principles of the Declaration of Helsinki, and local ethical and legal requirements. This trial is registered on ClinicalTrials.gov (NCT02264613).

The primary endpoints of the study were TEAEs, dose-limiting toxicities (DLT), and safety assessments. Secondary endpoints included overall response rate, time to response, duration of response, disease control rate, and duration of clinical benefit. Pharmacologic secondary endpoints included pharmacokinetic parameters of ALRN-6924 and its primary metabolite; serum levels of macrophage inhibitory cytokine-1 (MIC-1), an established secreted biomarker of p53 activation; and immunogenicity as measured by anti-drug antibody levels in blood.

Treatment continued until unacceptable toxicity, disease progression, or patient or physician decision to end treatment. Patients experiencing clinical benefit could continue the study despite radiographic disease progression.

The pharmacokinetic profiles of ALRN-6924 and its active metabolite ALRN-8714 in patient plasma were assessed using a validated liquid chromatography method with tandem mass spectrometric detection. Blood samples were obtained within 1 hour before the start and at the end of infusion (5 minutes) and at 0.5, 1, 2, 4, 8, 24, and 48 hours after infusion on cycle 1 day 1 in both arm A and arm B. In addition, selective sampling was done on subsequent dosing days in subsequent cycles of therapy in both regimens to evaluate accumulation of exposure, dose-to-dose variability, and changes in exposure due to possible induction or inhibition of clearance mechanisms. Pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin v.8.1 and included maximum plasma concentration (Cmax), area under the plasma concentration curve (AUC), and half-life calculations.

The pharmacodynamic profile of MIC-1 was assessed in patient serum samples using a validated, quantitative sandwich ELISA. Blood samples for serum MIC-1 levels were obtained in parallel with plasma pharmacokinetic samples at the collection times noted above.

Tumor response was assessed every 2 cycles (8 weeks) for patients in arm A and every 3 cycles (9 weeks) for patients in arm B. Response was determined by the investigators in accordance with RECIST 1.1 for patients with solid tumors (25) and IWG 2014 for lymphoma patients (26). Patients were considered eligible for response assessment if they had received at least one dose of ALRN-6924 and had undergone post-baseline radiological tumor assessment or exhibited clinical or objective progression as determined by the investigator and excluded patients with TP53-mutant tumors and patients in the lowest dose levels (

Patients were enrolled on the basis of either central or local laboratory TP53 assessment. Twenty-nine patients underwent both local and central laboratory testing, and 5 of these 29 patients (17.2%) had discrepant results (all TP53-WT on local testing and TP53-mutant on central testing), possibly due to differences in gene coverage between local and central laboratory assays and instances in which different biopsy samples (from primary tumor or metastases) were analyzed by the central and local laboratories. Details are provided in Supplementary Table S2. These patients who were TP53-WT on local testing but TP53-mutant on central laboratory assessment were excluded from the response-evaluable cohort.

Protocol-defined DLTs were experienced by 5 patients in treatment arm A. Dose escalation for this regimen proceeded to the 3.1 mg/kg dose level, wherein 9 patients were treated and only 1 experienced a DLT (i.e., grade 3 fatigue that did not respond to supportive treatment within 48 hours). Dose escalation then continued to 4.4 mg/kg, where four DLTs were noted among the 11 patients across both 1- and 2-hour ALRN-6924 infusions, including grade 3 anemia (n = 1), grade 3 hypotension (n = 1), grade 4 neutropenia (n = 1), and grade 3 elevated alkaline phosphatase level (n = 1). The patient with a DLT of grade 3 fatigue recovered following dose delay within the 7 days before the next clinical visit and continued treatment after dose reduction. The patient with grade 3 anemia continued treatment without dose reduction and without clinical symptoms or complications and recovered within 34 days. The patients experiencing DLTs of grade 3 hypotension and grade 4 neutropenia discontinued treatment and recovered within 5 and 7 days, respectively. The patient with a DLT of grade 3 elevated alkaline phosphatase level discontinued treatment and did not recover, and a subsequent liver biopsy revealed diffuse breast cancer metastases. On the basis of these DLTs, ALRN-6924 administered at 4.4 mg/kg once-weekly in arm A was considered to exceed the MTD and was not further explored. The safety, pharmacokinetic, pharmacodynamic, and antitumor activity of ALRN-6924 at doses up to 3.1 mg/kg was considered favorable for further exploration as a single-agent in specific tumor types and in combination studies with other anticancer agents. Although no DLTs were observed in arm B, and the efficacy profile in arm B was similar to that in arm A (vide infra), the twice-weekly regimen was considered less convenient than the once-weekly schedule and was not pursued.

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