Strong CYP3A4 Inhibitor Research Articles

Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the invivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers.

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. Invitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

Real-World Evidence Application in Translational Medicine: Making Use of Prescription Claims to Inform Drug-Drug Interactions of a New Psoriasis Treatment.

Patients with psoriasis often take multiple medications due to comorbidities, raising concerns about drug-drug interactions (DDIs) during the development of new medicines. DDI risk assessments of a new small molecule showed risks of CYP3A4 autoinduction and being a sensitive CYP3A4 substrate. We conducted a real-world evidence (RWE) claims analysis to assess the frequency of prescription claims for up to 12 months from the date of the initial psoriasis diagnosis for drugs that may interact with CYP3A4 substrates. We used 2013 to 2018 patient data from the US Merative MarketScan Research Database. Among patients diagnosed with psoriasis, less than 1% had a claim for a moderate/strong inducer, but up to 15% had a claim for moderate/strong inhibitor. Most prescriptions for CYP3A4 inhibitors or inducers included antibiotics and anticonvulsants. While CYP3A4 inducers were rarely used, those treated received more than >90 days treatment. Then, these RWE data were used to inform the early translational medicine strategy for the new investigational drug by strategically integrating DDI evaluations into a first-in-human healthy volunteer trial prior to studies in patients with psoriasis. The resulting DDI substudy showed that the investigational small molecule did not induce midazolam clearance but was sensitive to CYP3A inhibition, leading to the decision to exclude concomitant use of strong CYP3A4 inducers or inhibitors from clinical trials.

Pacritinib and concurrent azole antifungal therapy is deliverable in patients with hematologic malignancies.

Pacritinib is a novel kinase inhibitor approved for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis. Strong and moderate CYP3A4 inhibitors, such as some azole antifungals, are contraindicated or recommended to be avoided in combination with pacritinib, respectively. We aim to report our experience in patients who received pacritinib with concurrent azole antifungal therapy. We queried for patients with hematologic malignancies in the electronic medical record who received concurrent pacritinib and azole antifungal therapy. There were five cases of concurrent pacritinib and azole antifungal therapy in which none of the patients experienced grade 3 or higher non-hematologic toxicities. Some patients required dose modifications and/or interruptions in pacritinib therapy. This is the first clinical experience describing concurrent pacritinib and azole antifungals. Our experience shows that in the setting where this interaction cannot be avoided, concurrent administration is feasible with close monitoring and possible empiric dose reductions in select patients.

Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.

Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors. We retrospectively reviewed 40 patients between 2017-2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML. Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups. Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co-Administered with CYP3A4 Inhibitors.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.

The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239.

Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.

Repurposing ibrutinib for chemo-immunotherapy in a phase 1b study of ibrutinib with indoximod plus metronomic cyclophosphamide and etoposide for patients with childhood brain cancer.

TPS2703 Background: In children, brain cancer is the leading cause of cancer related death. The indoleamine 2,3-dioxygenase (IDO) pathway is a metabolic checkpoint, expressed by host myeloid and dendritic cells, that suppresses anti-tumor immune responses following chemotherapy. We recently published results of a first-in-children phase 1 trial (NCT02502708) that showed the oral IDO-pathway inhibitor indoximod was well tolerated and provided meaningful clinical benefit for many patients with progressive childhood brain tumors, when given in combination with oral chemotherapy regimens (1). Using preclinical models, we have also reported the importance of the Bruton’s Tyrosine Kinase (BTK) pathway as a key upstream driver of IDO during chemotherapy (2). Thus, we hypothesize that adding the BTK-inhibitor ibrutinib to the previously studied regimen of investigational indoximod IDO-inhibitor plus oral metronomic cyclophosphamide and etoposide will synergistically enhance anti-tumor immune responses, leading to improvement in Objective Response Rate (ORR) with manageable overlapping toxicity. Methods: The current study (NCT05106296) is an Investigator-Sponsored, open label, single-arm phase 1b trial comprised of a Dose-escalation Cohort (n=18) using a 3+3 dose escalation design to establish safety and dosing of ibrutinib in the combined regimen; followed by an Expansion Cohort (n=19) at the MTD to evaluate efficacy. Patients are treated with the all-oral 4-drug chemo-immunotherapy regimen in 28-day cycles using: (i) ibrutinib [Study Dose once daily on days 1-21]; (ii) indoximod [38.4 mg/kg/day divided twice daily throughout the cycle]; (iii) cyclophosphamide [2.5 mg/kg/dose, maximum dose 100 mg, once daily on days 1-21]; and (iv) etoposide [50 mg/m2/dose once daily on days 1-21]. Eligible patients are age 12 to 25 years with relapsed or refractory brain cancer, MRI evidence of current active disease not recently treated with radiation/proton therapy, ECOG performance score 0-2, and meet standard organ function requirements. Patients with systemic infection, autoimmune disease, recent live-virus vaccination, comorbid conditions that may overlap with expected regimen toxicities, or chronic treatment with anticoagulants or strong CYP3A inhibitors are excluded. Primary Objectives are to: (i) determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib for the combined regimen (Dose-escalation Cohort), and (ii) evaluate preliminary evidence of efficacy for the combined regimen in terms of ORR (Expansion Cohort). Exploratory analyses use single-cell RNA and TCR sequencing (scRNAseq/TCRseq) of cryopreserved serial peripheral blood samples to monitor for treatment-expanded TCR clonotypes and study their phenotype. 1. Neuro-Oncology 26:348-361, 2024. 2. Immunity54:2354-2371, 2021. Clinical trial information: NCT05106296 .

A first-in-human, phase 1, dose escalation study of SGR-2921 as monotherapy in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

TPS6590 Background: Cell division cycle 7-related protein kinase (CDC7) is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the CDC7's central role in maintaining replication fork integrity, chemical inhibition of CDC7 can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that SGR-2921 has potent anti-proliferative activity in AML cell lines representative of difficult to treat patient populations, agnostic of serious mutations (including those with p53 mutations), BTK resistance, and multiple prior lines of treatment. This anti-tumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. Methods: This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with relapsed or refractory (R/R) AML, high risk (HR) MDS, or very high risk (VHR) MDS. The study utilizes an accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event is observed. This is a multicenter global study (US, Spain and France). SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. A maximum of 144 patients will be enrolled into dose escalation and exploratory cohorts. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of SGR-2921 until the maximum tolerated dose (MTD) is exceeded. A RP2D will be selected from one of the tolerable dose levels. Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; active CNS leukemia; QTcF ≥470 msec. The primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and to identify the RP2D. Secondary objectives include evaluating SGR-2921 pharmacokinetics and investigating preliminary antitumor activity. Clinical trial information: NCT05961839 .

An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.

TPS7098 Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .

Peak study: A phase 3, randomized, open-label multi-center clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST).

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: &gt;1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .

Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.

A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating invitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.

A physiologically-based pharmacokinetic precision dosing approach to manage dasatinib drug-drug interactions.

Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration-time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%-80% for strong and 0%-70% for moderate CYP3A4 inhibitors and a 2.3-3.1-fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient-related factors, such as elevated gastric pH.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Abstract CT196: First-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors

Abstract Background: ATRN-119 is an orally bioavailable, potent, selective macrocyclic small molecule inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase. As the master regulator of DNA damage response (DDR), ATR orchestrates cellular response to DNA replication stress to preserve DNA replication fork integrity. Cancer cells with markedly increased oncogenic stress or dysfunctional DDR are more reliant on ATR for genome stabilization. Thus, inhibition of ATR can result in cancer cell-selective replication fork collapse and cancer cell death. Methods: This ongoing, first-in-human, multi-site phase 1/2a trial (NCT04905914) is investigating ATRN-119 safety and pharmacokinetic properties (primary objectives), preliminary efficacy in various solid tumors (secondary objective), and biomarker profile (exploratory objective). This study uses an open-label, standard 3+3 dose escalation and dose expansion study design. Key inclusion criteria include: advanced solid tumor, measurable disease (RECIST v1.1), tumor with at least 1 DDR mutation by next-generation-sequencing, at least 1 failed standard-of-care therapy, ECOG PS 0 or 1, and adequate organ function. Key exclusion criteria are cancer therapy within 4 weeks or at least 5 half-lives, unresolved therapy-related AEs, investigational agent within 5 half-lives or 30 days of study drug, CNS metastases or unstable involvement, and concomitant treatment with strong CYP3A4 or CYP2D6 inhibitors or inducers. Results: This trial is currently enrolling at Dose level 5 (550 mg). Among 12 patients in the first four dose levels, the median age is 62 years (range: 48 to 79), where 67% (n=8) are female, 75% (n=9) are White, and 25% (n=3) are Black. The median number of prior treatments is 3 (range: 1 to 6, and 92% have received platinum-based chemotherapy). The majority of tumors, 75% (n=9), had a TP53 mutation. There have been no reports of dose-limiting toxicities, treatment-related serious adverse events (AE), and treatment-related AEs Grade 3 or higher in these cohorts. The three most commonly reported all-cause AEs are fatigue (33%, n=4), nausea (25%, n=3), and diarrhea (25%, n=3). Increasing exposure and maximum serum concentrations (Cmax) were observed by dose level. The half-life of ATRN-119 is ~5 hours. Two of 12 patients achieved stable disease (SD): one patient from Dose level 1 (50 mg) who progressed on Day 112 and one patient from Dose level 3 (200 mg) who remains on treatment as of Day 118 (data cut off date: January 2, 2024). Conclusion: In these early cohorts, once-daily oral ATRN-119 appears to be well tolerated with a manageable safety profile, exhibits near dose proportionality, and demonstrates disease stabilization warranting further investigation. Further studies to explore a twice-daily schedule are being considered. Citation Format: Fiona Simpkins, Amit Mahipal, Patricia LoRusso, Reva Schneider, Crystal Miller, David Stenehjem, Eric J. Brown, Mike Carleton, Joachim Gullbo, Nadeem Q. Mirza. First-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT196.

Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200mg of itraconazole, a strong CYP3A4 inhibitor, on 360mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960mg of sotorasib PKs was interrogated after a single dose of 600mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.

SWOG S2200 (PAPMET2): A phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC).

TPS493 Background: The role of immune therapy is not established in PRCC. The S1500 (PAPMET) clinical trial established single agent cabozantinib as the standard of care for PRCC (PMID 33592176) with a median progression free survival (PFS) of 9.0 months compared to 5.6 months with sunitinib. Trials have shown activity of PD-(L)1 antagonists as monotherapy (PMID 33529058) or in combination with targeted therapy (PMID 34491815). In a single arm study of cabozantinib/nivolumab the median PFS was 12.5 months (PMID 35298296). There are no prior randomized studies of immune therapy in PRCC. Single arm trials often overestimate the true effect size (PMID 31218346), highlighting the unmet clinical need for a randomized clinical trial in PRCC. We hypothesize that the combination will have higher clinical activity than single agent cabozantinib. Methods: This is a prospective randomized phase II clinical trial conducted through the NCTN and led by SWOG. The primary endpoint is a comparison of PFS between cabozantinib and cabozantinib/atezolizumab. Secondary endpoints include comparison of objective response rate, overall survival and safety. Patients are treated with cabozantinib 60mg/day versus cabozantinib 60mg/day + atezolizumab 1200 mg q3 weeks. 200 patients will be enrolled and randomized 1:1. Key inclusion criteria include a pathologic confirmation of PRCC; presence of metastasis; 0-1 prior systemic lines of therapy for metastatic disease; and measurable disease as defined by RECIST 1.1 criteria. Prior treatment with adjuvant pembrolizumab is allowed if completed greater than 6 months before enrollment. Key exclusion criteria include clinically significant autoimmune disease; ongoing use of strong CYP3A4 inhibitors, strong CYP3A4 inducers. Planned correlatives include stool microbiome testing and genomic/transcriptomic analysis from blood and baseline tissue assays. Clinical trial information: NCT05411081 .

Quantification of midostaurin in plasma and serum by stable isotope dilution liquid chromatography-tandem mass spectrometry: Application to a cohort of patients with acute myeloid leukemia.

Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors. A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections. Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens. In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach.

Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. Invitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC∞] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC∞ ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC∞ by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC∞ by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC∞) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600mg once daily (QD) during cycles of 21days on/7days off, with optional dose reduction to 400 mgand 200mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4h, mean half-life of 32.0h and oral bioavailability of 65.8% at 600mg. It is eliminated mainly by hepatic metabolism (~84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600mg QD starting dose, with potential individualized dose reductions to 400 mgand 200mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.