Intermittent Schedule Research Articles

Thermal comfort analysis of historical mosques. Case study: The Ulu mosque, Manisa, Turkey

Mosques are sanctuary places for Muslims where they can perform their religious activities and also can communicate with each other. On the other hand, historical mosques may contain artworks which have cultural heritage values. These mosques originally have not any Heating, Ventilating and Air-Conditioning systems. For this reason, obtaining thermal comfort becomes a significant issue. In this study, a systematic approach on monitoring and evaluating thermal comfort of historical mosques were developed. As a case study, The Ulu Mosque, Manisa/Turkey was monitored from 2015 to 2018, and thermal comfort evaluation of the mosque was conducted during prayer times based on the method provided by ISO 7730. A dynamic Building Energy Performance Software, DesignBuilder, was used to model the mosque, and the model was calibrated by using hourly indoor temperature data. The calibrated model was then used to evaluate existing conditions of the mosque and develop retrofitting scenarios in order to increase thermal comfort of prayers. Thirteen different scenarios were proposed to improve thermal comfort of prayers during worship periods. The results were evaluated according to EN 16883 for conservation of cultural heritage of the mosque. Electrical radiator heating with intermittent operating schedules was obtained as the best scenario to protect cultural heritage via artworks, while decreasing disssatisfaction level of the prayers from 45% to 10% in winter months. Additionally, intermittent operation saved 46.9% of energy compared to continuous operating schedule.

518MO Tolerability and preliminary clinical activity of SY-5609, a highly potent and selective oral CDK7 inhibitor, in patients with advanced solid tumors

SY-5609 is a highly potent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. Initial phase 1 results of SY-5609 in patients (pts) with advanced solid tumors reported proof of mechanism with dose-dependent effects on a pharmacodynamic (PD) gene expression marker POLR2A mRNA at 3 mg/day, the maximum tolerated dose (MTD) of the continuous daily dosing schedule. Additional data from the ongoing study, including from intermittent dosing schedules, are reported.

Discrete ARMA Model Applied for Tumor Growth Inhibition Modeling and LQR-based Chemotherapy Optimization

Mathematical models for tumor growth inhibition (TGI) are an important tool in the battle against cancer allowing preclinical evaluation of potential anti-cancer drugs and treatment schedules. In this article, an autoregressive moving average (ARMA) model for cancer tumor growth is estimated based on laboratory data of TGI in mice and presented. The model was proven capable of describing with accuracy the tumor growth under single-agent chemotherapy. At the same time, an optimal control problem was formulated to identify optimal drug dosages. The linear quadratic regulator (LQR) controller was used with success in optimizing both periodic and intermittent chemotherapy treatment schedules reducing the tumor mass while keeping dosages under acceptable toxicity

Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Maintenance versus discontinuation of androgen deprivation therapy during continuous or intermittent docetaxel administration in castration-resistant prostate cancer patients: A multicentre, randomised Phase III study by the Piemonte Oncology Network

BackgroundThis study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. Patients and methodsmCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. ResultsThe trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72–1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55–1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. ConclusionsThis trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.

A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma

BackgroundWhen treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results. Patients and MethodsPatients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability. ResultsTen patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively. ConclusionCopanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing.

Abstract 2077: Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC

Abstract Introduction: BAY2402234 is a potent and specific orally administered inhibitor of dihydroorotate dehydrogenase (DHODH) which showed anti-tumor activity in preclinical models of AML and is under clinical evaluation in myeloid malignancies (NCT03404726). Small cell lung cancer (SCLC) is a highly metastatic malignancy (the brain being a frequent metastatic site), which carries a dismal clinical prognosis. Previous preclinical research indicated that SCLC was particularly sensitive to DHODH inhibition, and in the current investigation the activity of BAY2402234 in this tumor indication was evaluated. Experimental Procedures: A variety of in vivo models derived from human SCLC samples were evaluated: (1) cell-line derived xenograft (CDX) subcutaneous models; (2) a CDX intracranial model; and (3) patient-derived xenograft (PDX) subcutaneous models. As is typical for SCLC, most of these models harbored mutations in both p53 and Rb1. BAY2402234 was administered orally either once daily or on an intermittent schedule (4 days on/3 days off). Standard-of-care (SoC) therapies were included in some experiments. Tumor tissue and plasma were collected for pharmacodynamic analyses. Results: In subcutaneous CDX models, BAY2402234 exhibited robust anti-tumor activity, including tumor regressions in some models. Strong anti-tumor activity was also observed in various subcutaneous PDX models, including activity in a model resistant to SoC therapy. In an intracranial tumor model, BAY2402234 significantly enhanced survival compared to the vehicle-treated cohort. Both dosing schedules tested were well-tolerated and highly active. Pharmacodynamic analyses to quantify the level of target inhibition observed in the various models are ongoing. Conclusions: The results of this investigation confirm and extend previous preclinical results and indicate that BAY2402234 may represent a novel treatment for SCLC, including patients with brain metastases. RESTRICTED Citation Format: Stefan Kaulfuss, Andreas Janzer, Gerhard Siemeister, Renan Borowicz, Katrin Jaensch, Katrin Gutberlet, Ricarda Schlenz, Andrea Triller, Ashley Eheim, Michael Jeffers, Sven Christian. Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2077.

Abstract 1141: CDK9 inhibition is selective for transcriptionally addicted tumors harboring MYC genomic amplifications

Abstract Transcriptional deregulation is a hallmark of many cancers, including a subset that are “transcriptionally addicted” and depend on high levels of transcription for oncogenic program genes. Although these tumors are thought to be highly susceptible to targeting of the transcriptional apparatus, their molecular definition remains challenging. To better define molecular sensitivity to transcriptional inhibition, we profiled pan-cancer sensitivity to KB-0742 — a potent, selective, and orally bioavailable small molecule inhibitor of the transcription elongation cofactor CDK9. Multiplexed sensitivity profiling across ~1,000 adherent and suspension immortalized cell lines using the Broad PRISM platform revealed lineage and molecular determinants of sensitivity. Consistent with prior reports, MYC genomic amplification emerged as a key driver of CDK9 inhibitor sensitivity, and this was especially pronounced in non-small cell lung cancer. Sensitivity to CDK9 inhibition was further observed in MYC amplified/over-expressed ex vivo primary patient tumor cell cultures and patient-derived xenografts. Analysis of the temporal kinetics of CDK9 inhibition revealed a rapid collapse of oncogenic transcription programs comprised largely of short half-life transcripts including key oncogenes such as MYC and MCL1. In CDK9 sensitive ex vivo and in vivo models, suppression of oncogenic transcription for >8 hours was followed by apoptosis. In ex vivo models, CDK9 inhibitor sensitivity was observed for both treatment naïve and heavily pretreated patient samples. For in vivo models, CDK9 inhibition on an intermittent dosing schedule achieved sustained target coverage, as evidenced by both direct readouts of CDK9 activity and corresponding transcriptional response, and ultimately resulted in sustained tumor growth inhibition in multiple solid tumor types. These data suggest that MYC genomic amplification may serve as an important feature defining sensitivity to CDK9 inhibition in patients with advanced solid tumors. Citation Format: Melinda A. Day, Nikolaus D. Obholzer, Akanksha Pandey, Tom Chen, Tong Liang, Rosa A. Villagomez, Mulini Pingili, Jost V. Koren, David B. Freeman, Holly M. Nguyen, Jennifer L. Conor, Eva Corey, Matthew G. Reese, Andrew Boghossian, Brienne Engel, Melissa M. Ronan, Jennifer A. Roth, Joesph P. Vacca, Peter B. Rahl, Marius S. Pop, Benjamin W. Trotter, Charles Y. Lin, Jorge C. DiMartino, Pavan Kumar, Douglas C. Saffran. CDK9 inhibition is selective for transcriptionally addicted tumors harboring MYC genomic amplifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1141.

Abstract LB001: Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers

Abstract RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node regulating RAS signaling. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Here we report data from the dose-escalation phase of this study. A total of 104 patients were dosed across three schedules: daily dosing (n = 49) and two intermittent dosing schedules, twice weekly on D1D4 (n = 31) or D1D2 (n = 24). Based on PK and tolerability, the recommended phase 2 dose and schedule (RP2DS) was determined to be 200 mg D1D2, delivering a 400 mg weekly dose intensity. Of the 80 efficacy evaluable patients, there was 1 CR (NF1LOF uterine carcinosarcoma), 1 PR (KRASG12C NSCLC), and 1 unconfirmed PR (KRASG12D NSCLC). Tumor regressions were observed in another 11 patients (-2.4% to -27.1%). Disease control rate was 61% (23/38) in patients with KRASMUT NSCLC and 80% (12/15) in KRASG12C NSCLC specifically. The safety and tolerability profile of RMC-4630 were consistent with the mechanism of action and RAS pathway inhibition. The most frequent adverse events (AEs) were edema (48%), diarrhea (47%), fatigue (36%), anemia (34%), and thrombocytopenia (33%). Most AEs were grade 1 or 2 and were manageable. Intermittent dosing with either D1D2 or D1D4 weekly was generally better tolerated than daily dosing at an equivalent weekly dose intensity. Plasma concentrations of RMC-4630 after dosing with 200 mg D1D2 were above those predicted to be clinically active based on preclinical models. Cmax reached and often exceeded the ‘apoptotic threshold' defined as plasma exposures that were associated with induction of tumor regressions in preclinical models. Trough concentrations at the end of each week were at or around the EC50 for RAS pathway inhibition in tumor which is predicted to be sufficient to allow normal tissue recovery and therefore maintain tolerability with sustained dosing up to 6 months. Sequential analysis of pERK levels in peripheral blood cells and paired pre- and on-treatment tumor biopsies showed evidence of RAS pathway inhibition. Tumor and blood-based immune-oncology biomarkers showed preliminary evidence of anti-tumor immune activation. Longitudinal analysis of circulating tumor DNA indicated molecular responses consistent with anti-tumor activity in tumors carrying specific driver mutations in the RAS signaling pathway. An expansion cohort of patients with gynecologic cancers with NF1LOF is underway with monotherapy at the RP2DS. RMC-4630 continues to be evaluated in combination with the MEK inhibitor cobimetinib (Cotellic), the KRASG12C(OFF) inhibitor sotorasib, the PD1 inhibitor pembrolizumab (Keytruda) and the EGFR inhibitor osimertinib (Tagrisso). Additional combination studies are also planned. Citation Format: Marianna Koczywas, Eric Haura, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Richa Dua, Zhengping Wang, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari, Xiaolin Wang, S Ignatius Ou. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB001.

Abstract CT019: A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Evaluation of efficacy in KRAS mutated NSCLC

Abstract Background KRAS is a known oncogenic driver in non-small cell lung cancer (NSCLC), with KRAS G12C and G12V mutations occurring in ~13% and ~7% of the of NSCLC ( adenocarcinoma subtype). The dual RAF-MEK inhibitor VS-6766 has shown single agent activity against G12V KRAS mutated NSCLC (Guo C et al Lancet Oncology 2020, 21:1478-88). Based on pre-clinical data, we hypothesised that augmented focal adhesion kinase (FAK) signalling is a mechanism of resistance to MEK inhibition and devised the current clinical trial. We have previously reported the safety of an intermittent schedule of the combination of VS-6766 and the FAK inhibitor defactinib and its efficacy in low grade serous ovarian cancer (Shinde et al., AACR 2020). We now report the activity of the combination in KRAS mutated NSCLC. Methods Patients were treated with an intermittent dose of drugs VS-6766 at 3.2 - 4 mg twice a week and defactinib 200 mg twice daily in the dose escalation and expansion cohorts of the study. Both drugs were administered three weeks on/one week off in 28-day cycles. We aim to recruit 20 patients with KRAS mutated NSCLC in an expansion cohort. Results To date, 19 patients with KRAS mutated NSCLC have been treated in the dose escalation and expansion cohorts. All patients had been previously treatment with a PD-1 or PDL-1 targeting immune checkpoint inhibitor. The median age was 64 years (22 - 73), M/F ratio was 7/12, and the median prior lines of treatment was 3. Currently, 17 of 19 patients have had at least one re-staging assessment, 2/17 (12%) patients had a partial response and 10/17 (59%) had stable disease as their best response. Of note, 11/17 (65%) patients had a degree of reduction in size of their tumours and 5/17 (29%) have been treated for 6 months or more with 3 patients still on treatment. Interestingly, 2/2 (100%) of the KRAS G12V NSCLC patients showed a partial response. Conclusions Developing new treatments for non-G12C KRAS mutated NSCLC is an area of unmet need. The combination of VS-6766 and defactinib treatment in cohorts of patients with NSCLC pre-treated with chemotherapy and immunotherapy has shown anti-tumour activity in subsets of patients with KRAS mutated NSCLC, in particular those with tumours harbouring KRAS G12V mutations. A registration-directed study evaluating VS-6766 ± defactinib for treatment of recurrent NSCLC with KRAS G12V mutation (NCT04620330) has been initiated Citation Format: Matthew G. Krebs, Rajiv Shinde, Rozana Abdul Rahman, Rafael Grochot, Martin Little, Jenny King, Joseph Kitchin, Mona Parmar, Alison Turner, Muneeb Mahmud, Christina Yap, Nina Tunariu, Juanita Lopez, Johann S. De Bono, Udai Banerji, Anna Minchom. A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Evaluation of efficacy in KRAS mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT019.

A Phase II Study to Determine the Safety and Efficacy of the Dual m-TORC Inhibitor AZD2014 and to Investigate Additional Toxicities in Combination with Rituximab in Relapsed/Refractory Diffuse Large B Cell Lymphoma (DLBCL)

A Phase II Study to Determine the Safety and Efficacy of the Dual m-TORC Inhibitor AZD2014 and to Investigate Additional Toxicities in Combination with Rituximab in Relapsed/Refractory Diffuse Large B Cell Lymphoma (DLBCL)

A Novel Gene Expression Classifier Enriches for Single Agent Clinical Activity of CC-122, a Cereblon Modulator, Administered Orally to Relapsed or Refractory Diffuse Large B-Cell Lymphoma Subjects: Results from the Phase I CC-122-ST-001 Study

A Novel Gene Expression Classifier Enriches for Single Agent Clinical Activity of CC-122, a Cereblon Modulator, Administered Orally to Relapsed or Refractory Diffuse Large B-Cell Lymphoma Subjects: Results from the Phase I CC-122-ST-001 Study

Efficacy of Copanlisib Monotherapy in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Subset Analysis from the CHRONOS-1 Trial

Efficacy of Copanlisib Monotherapy in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Subset Analysis from the CHRONOS-1 Trial

Updated Safety and Efficacy from the Copanlisib CHRONOS-1 Trial in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma: Low Incidence of Late-Onset Severe Toxicities

Updated Safety and Efficacy from the Copanlisib CHRONOS-1 Trial in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma: Low Incidence of Late-Onset Severe Toxicities

A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer

IntroductionMEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). MethodsA standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. ResultsThirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months–NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1–mutated patients, the ORR was 42.8%. ConclusionThe addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.

Results of phase II randomized study of intermittent versus continuous schedule of vemurafenib plus cobimetinib in BRAF-mutated advanced melanoma.

9528 Background: Combination of vemurafenib plus cobimetinib is approved for the treatment of BRAF-mutated advanced melanoma. Although patients initially respond to treatment, resistance emerges before 18 months in most cases. One of the key pre-clinical observations that supported an intermittent schedule was that resistant tumors suffer a fitness deficit in the absence of the drug, so modulation of the drug pressure through an intermittent dosing could delay the emergence of resistance. Methods: GEM1501 is a randomized phase 2 study comparing the activity of the combination of vemurafenib 960 mg every 12 h/d plus cobimetinib 60 mg/d in a standard (arm A) versus intermittent schedule (arm B). Arm A: four-week (w) cycles of daily vemurafenib for 4w plus cobimetinib for 3w-on and 1w-off-treatment. Arm B: first three cycles according to the standard schedule, followed by 6w-cycle with 2w-off vemurafenib & 3w-off cobimetinib. Primary endpoint was progression free survival (PFS) and secondary were objective response (OR) and treatment-related adverse events (TAEs). Results: 70 treatment-naïve patients were included. Results in arms A and B: median PFS 16.2 (95%CI 9.5, 24.1) vs 6.9 months (95%CI 5.2, 9.3) (p = 0.079); OR in 25 (71.4%) (8 complete -23%-) vs 21 (60%) patients (5 complete -14%-); G3-4 TAEs 42.8% vs 40.0%, respectively. Analysis of BRAFV600 mutation in tumoral cell free DNA (cfDNA) was performed in serial plasma samples in 41 patients. Twenty-one (51%) patients had detectable BRAFV600 mutation in pretreatment cfDNA (preBRAF+). Significant differences in PFS were found according to preBRAF V600: 8.2 months (95%CI 5.2, 13.6) in preBRAF+ vs non-reached (NR) (95%CI 2.8, NR) in preBRAF- (p = 0.017). In arm A, median PFS was 13.3 months (95% CI 4.6, NR) in preBRAF+ vs NR (95% CI 2.3, NR) in preBRAF-. In arm B, median PFS was 6.2 months (95% CI 0.3-8.3) in preBRAF+ vs NR (95%CI 2.8, NR) in preBRAF- (p = 0.003). BRAFV600 mutation became undetectable in cfDNA after treatment initiation in all preBRAF+ patients. Different kinetic of BRAFV600 mutation in cfDNA was found according to treatment arm. At progression, BRAFV600 reappeared in cfDNA in all (5/5) cases treated in arm B, but only in 50% (3/6) of cases in arm A. NGS analysis of cfDNA at progression suggested different resistance mechanisms. Conclusions: The results of this study do not support the use of an intermittent schedule of vemurafenib plus cobimetinib in advanced melanoma. BRAFV600 detection in pretreatment cfDNA is a prognostic factor of poor survival that it is independent of treatment schedule, although most striking differences favoring continuous arm vs intermittent arm were found in patients with detectable BRAFV600 mutation on pretreatment cfDNA. Further research is required to determine the clinical value of the analysis of resistance mechanisms in cfDNA. Clinical trial information: 2014-005277-36.

Efficacy and safety of the PI3Kδ inhibitor zandelisib (ME-401) on an intermittent schedule (IS) in patients with relapsed/refractory follicular lymphoma (FL) with progression of disease within 24 months of first-line chemoimmunotherapy (POD24).

7550 Background: FL patients (pts) with POD24 have poorer survival and may benefit from novel therapies at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study for FL demonstrating a high objective response rate (ORR) and well tolerated when given on IS (J Clin Oncol 2020;38:#8016). We report here results based on POD24 status (NCT02914938). Methods: Eligible pts had ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3K therapy. Zandelisib was administered at 60 mg once daily for 8 weeks followed by IS on days 1-7 of each subsequent 28-day cycle, either as monotherapy or with rituximab at 375 mg/m2 for 8 doses in Cycles 1-6. Treatment was continued until disease progression, intolerance, or withdrawal of consent. Imaging scans were obtained after 2 and 6 cycles, and then every 6 cycles. Response was reported based on Lugano criteria. Results: 37 FL pts were enrolled and received zandelisib on IS as monotherapy (N = 18) or in combination with rituximab (N = 19). Median number of prior therapies = 2 (range, 1-5). The ORR was 86.5% (32/37) with 27% CR (complete response). In the monotherapy group the ORR and CR were 77.8 % (14/18) and 27.8% and with rituximab 94.7% (18/19) and 26.3% respectively. Median duration of response (DOR) among all pts was not reached with a median follow-up of 16.9 months (mos) (1.2-33.1+). 22 pts (59%) were POD24, of which 15 (68%) had ≥2 prior lines of therapy. Despite more refractory disease, ORR among the POD24 pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%) discontinued therapy due to an adverse event (AE) for any cause. Grade (Gr) 3 AE of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3 (8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no pulmonary infection. Conclusions: Zandelisib administered on IS as monotherapy or with rituximab resulted in a high-rate of durable responses in FL, both in POD24 and non-POD24 groups and therapy was well-tolerated with low rate of Gr 3 class-related AESI and discontinuation rate due to AE’s. Zandelisib as monotherapy is being evaluated in a global Phase 2 study in FL and MZL after failure of 2 prior therapies (NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL and MZL after failure of prior immunochemotherapy will begin enrollment in 2021. Clinical trial information: NCT02914938. [Table: see text]

A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumors.

3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 is a member of the monoPARP class of enzymes and a newly identified negative regulator of nucleic acid sensing in tumor cells. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in multiple cancers. RBN-2397 is a potent, selective inhibitor of PARP7. In preclinical models, RBN-2397 restored Type I IFN signaling in tumors, caused complete tumor regressions, and induced adaptive immunity. Methods: Patients (pts) with advanced solid tumors were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3+3 dose escalation design. Primary objective: establish MTD and/or RP2D. Secondary obj.: safety, activity, PK of unmicronized/micronized tablets. Exploratory obj.: Pd. Results: As of 4 January 2021, 47 pts were treated: 25 pts in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID). The most frequent RBN-2397-related AEs (all grades) were dysgeusia (26%), decreased appetite (13%), fatigue (11%), and diarrhea (11%). Gr 3/4 RBN-2397-related AEs all occurred in 7 pts (15%) at doses ≥ 200 mg: diarrhea (2 pts, 4%), increased ALT, AST, and bilirubin (1 pt, 2%), and fatigue, anemia, neutropenia, and thrombocytopenia in 1 pt (2%) each. The 2 DLTs were Gr 3 febrile neutropenia (400 mg continuous schedule) and Gr 4 increase in ALT/AST (500 mg intermittent schedule). Plasma exposures generally increased dose dependently with the majority at or above the projected efficacious range based on animal studies. All evaluable baseline tumor biopsies showed evidence of PARP7 expression as measured by mRNA in situ hybridization (n = 11; Median tumor H score: 128). In 5 evaluable tumor biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I IFN. CXCL10 mRNA increased in all evaluable on-treatment biopsies (1.5 to 8-fold). Several on-treatment biopsies showed enrichment for immune response gene sets that was accompanied by an increase in CD8+ T cells and Granzyme B expression, evidence for induction of an adaptive immune response post RBN-2397. This increase in immune response related genes and CD8+ T cells was observed in a pt with metastatic squamous NSCLC who has been on study for 16+ months. 1 pt with HR+, HER2- breast cancer achieved a confirmed PR at 100 mg and 8 pts had SD for ≥18 weeks (RECIST 1.1). Conclusions: To date, RBN-2397 is well tolerated and demonstrates dose dependent increases in plasma exposures, evidence of target inhibition, and preliminary signs of clinical activity. Determination of MTD/RP2D is imminent and study expansion is planned to evaluate safety and efficacy in squamous NSCLC, HNSCC, HR+ breast cancer, and PARP7 amplified tumors. Clinical trial information: NCT04053673.

Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL).

TPS7573 Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor, achieved an 87% response rate, with median duration of response not reached in iNHL when given as a monotherapy or in combination with R. A low rate ( < 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors is observed in patients administered zandelisib on an intermittent schedule (IS) (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with iNHL. Key eligibility criteria: adults with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects will be randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given in a 28-day cycle comprising of daily dosing for 2 cycles followed by IS dosing on days 1-7 of each 28-day subsequent cycle for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial will enroll approximately 534 pts in ̃200 sites globally and will begin enrollment in mid-2021. Clinical trial information: NCT04745832.