Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.

Prehospital emergency medicine for children receiving palliative home care in Germany-a cross-sectional, exploratory study of EMS providers.

Background: The prevalence of children with life-limiting conditions is rising, and since the amendment of the social insurance code in Germany, palliative home care teams have treated an increasing number of children. These teams provide 24/7 readiness, yet some parents still call the general emergency medical service (EMS) for various reasons. EMS is exposed to complex medical problems in rare diseases. Questions arose about the experiences of EMS and whether they felt prepared for emergencies involving children treated by a palliative care team. Methods: This study used a mixed methods approach to focus on the interface between palliative care and EMS. First, open interviews were conducted, and a questionnaire was developed based on the results. The variables included demographic items and individual experiences with patients. Second, a case report of a child with respiratory insufficiency was presented to assess the spontaneous treatment intentions of EMS providers. Finally, the need, relevant topics, and duration of specific training in palliative care for EMS providers were evaluated. Results: In total, 1,005 EMS providers responded to the questionnaire. The average age was 34.5 years (±10.94SD), 74.6% were male. The average work experience was 11.8 years (±9.7), 21.4% were medical doctors. Experience with a call of a life-threatening emergency involving a child was reported by 61.5% and severe psychological distress during such a call was reported by 60.4%. The equivalent distress frequency for adult patient calls was 38.3%. (p < 0.001). After review of the case report, the EMS respondents suggested invasive treatment options and rapid transport to the hospital. Most (93.7%) respondents welcomed the consideration of special training in pediatric palliative care. This training should include basic information about palliative care, an analysis of cases involving palliatively treated children, an ethical perspective, practical recommendations, and available (24/7) local contact for further guidance and support. Conclusion: Emergencies in pediatric palliatively treated patients were more common than expected. EMS providers perceived the situations as stressful, and there is a need for specific training with practical aspects.

Vaccine Preventable Diseases in Pediatric Palliative Care - A Multicenter Cross-Sectional Study.

CONTEXT: Vaccine preventable diseases lead to distressful symptoms and complications among pediatric patients receiving specialized home palliative care. There was no data on the vaccination compliance. OBJECTIVES: The objective was to determine the vaccination coverage, discuss the relevance of vaccinations and provide vaccination recommendations in pediatric palliative care. METHODS: Vaccination data were compared in a multicenter cross-sectional study. Expert interviews were conducted to evaluate symptom burden. The vaccination status of patients treated by six German pediatric specialized home palliative care teams was recorded from January 2019 to December 2019. The data were compared to the national immunization schedule and the vaccination rate of a representative German pediatric cohort. Onset of missed vaccination was compared to the date of diagnosis of the life-limiting condition. A risk score was calculated to evaluate the relevance of each individual vaccinations. RESULTS: Vaccination rates of Tdpa, haemophilus influenzae type B, poliomyelitis, hepatitis B, pneumococcal disease, meningococcal diseases type C, and MMR were lower compared to healthy controls. There were no significant differences in varicella. In most cases the discontinuation of recommended immunizations occurred after diagnosis of the palliative condition. Influenza had the highest risk score and was the most frequent vaccine preventable disease in retrospective data. This paper includes a pragmatic proposal for the management of vaccination in this vulnerable population. CONCLUSION: Children and adolescents with life-limiting conditions are at increased risk of vaccine preventable diseases. Individual vaccination counselling is recommended.

Co-clinical Modeling of the Activity of the BET Inhibitor Mivebresib (ABBV-075) in AML.

BACKGROUND/AIM: The therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML). MATERIALS AND METHODS: Co-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%). RESULTS: Results from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively). CONCLUSION: These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment.

Adverse Events in Placebo Arms of Cancer Trials.

BACKGROUND/AIM: Adverse events (AEs) in cancer trials may be caused by the investigational agents or the underlying disease. Determining the causality is challenging, especially in early cancer drug development when a control arm is lacking. MATERIALS AND METHODS: We carried out a systematic literature review of AE frequencies in placebo arms of randomized trials for malignant solid tumors and hematologic malignancies reported in PubMed from 2016 to January 2022. RESULTS: Among 148 placebo arms, the AEs with the highest reported mean frequencies among all publications were: Fatigue (20.1%), nausea (16.3%), diarrhea (14.3%), abdominal pain (12.4%), and anemia (10.9%); AEs resulting in drug discontinuation were reported in 5.6% of placebo-treated patients and serious AEs in 18.7% of placebo patients. CONCLUSION: The data presented here may be used as a benchmark to help assess drug causality in early development cancer studies without a control arm.

Final results of the Choroid Plexus Tumor study CPT-SIOP-2000.

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation.

Fatigue in Cancer Treatment Studies: Analysis of Placebo Arms.

BACKGROUND/AIM: Fatigue and asthenia are common in patients with cancer; and identifying the cause as drug toxicity versus cancer progression is difficult, particularly in clinical trials without control arms. MATERIALS AND METHODS: We carried out a systematic literature review of fatigue in placebo arms of randomized cancer trials reported in PubMed from 2000 to 2021. RESULTS: Fatigue/asthenia were reported in 100 out of 134 placebo cohorts, and the average of reported frequencies was 22.8%, with a range of 0-83%. Grade 3 or higher fatigue/asthenia was reported in 2.3% (0-17%). Fatigue/asthenia was positively correlated with nausea (R=0.683) Conclusion: For detection of drug toxicity, observations should be flagged when they are higher than the maximum reported in the placebo arm, and the assessment should be supplemented by comparing observations in early oncology trials to literature placebo arms, including both sample sizes and event numbers.

Anemia in Placebo Arms of Cancer Studies.

BACKGROUND/AIM: Adverse event (AE) frequencies observed in interventional clinical trials are difficult to interpret when the placebo control is missing. MATERIALS AND METHODS: Systematic literature review of AEs reported from the placebo arms of randomized cancer trials between 2008 and 2021. Imputation of missing values assuming normal distribution of hemoglobin values. RESULTS: Anemia grade 1 or higher was reported in 46 of 100 placebo monotherapy cohorts with a mean frequency of 23.4% (SD=27%) of the enrolled patients. The reported frequency depended on the type of cancer; other demographic variables had no significant influence on anemia frequency. CONCLUSION: External controls for anemia in clinical trials should be disease specific.

[Interdisciplinary expert consensus on innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer]. / Interdisziplinärer Expertenkonsensus zu Innovationen der bildgebenden Diagnostik und radionuklidbasierten Therapien des fortgeschrittenen Prostatakarzinoms.

BACKGROUND: Numerous diagnostic and therapeutic innovations in the treatment of advanced prostate cancer, both in the hormone-sensitive and in the castration-resistant situation, recently led to a new orientation in the management of this tumor. However, there are potential indications beyond the ones covered by the S3 guideline on early detection, diagnosis and therapy of prostate cancer in clinical care that might be helpful for patients. OBJECTIVES: Since July 2018, an interdisciplinary group of experts from nuclear medicine, radiologists, radio-oncologists and urologists developed a consensus paper on state-of-the-art innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer. CONCLUSIONS: Provided by the working group are suggestions and strategies to improve the implementation of new imaging techniques such as multiparametric magnetic resonance imaging (mpMRI), PSMA-PET/CT (prostate-specific membrane antigen-positron emission tomography/computed tomography) and innovative therapeutic options (radium-223 dichloride, lutetium-177-PSMA) in the complex treatment of metastatic castration-resistant prostate cancer (mCRPC).

Headache Reporting in Oncology Trials Depends on the Demographics of the Study Population.

BACKGROUND/AIM: The frequency of adverse events (AEs) in clinical trials without control arms is difficult to interpret. MATERIALS AND METHODS: This is a systematic literature review of AEs reported from the placebo arms of randomized cancer trials in PubMed between 2008 and 2020. RESULTS: We found 80 placebo patient cohorts in 73 publications, describing 17,968 subjects who received placebo. Headaches were reported in 35 patient cohorts with an average frequency of 12.3% (+/- SD=8.0, range=0.4-34.1), and were more common in cohorts with a median age between 45 and 50 years, with higher performance status, and breast cancer (average 29.8% +/- SD=6.1). AEs leading to discontinuation were reported in 5% of cohorts (+/- SD=5.1, range=0-22.7). CONCLUSION: Considering covariates allows more accurate interpretation of the observed AE frequencies in cancer trials.

A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach. METHODS: In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg). RESULTS: Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure. CONCLUSIONS: Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML. LAY SUMMARY: Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.

Clinical characteristics, late effects and outcomes in pineoblastomas in children: a single center experience.

BACKGROUND: Pineoblastomas (PB) are rare tumors of the central nervous system and are more common in children. There is no consensus about standard of care. The objective of this study is to analyze the outcome of children with PB. METHODS: Six patients with PB who were diagnosed between 1990-2012 were evaluated retrospectively. Demographics, age of diagnosis, first complaint, tumor region, diagnosis type, seeding metastasis to the spinal axis or cerebrospinal fluid (CSF), treatment and survival of these patients were recorded. RESULTS: Three patients had subtotal resection and all patients received chemotherapy and craniospinal irradiation (CSI) after diagnosis. Median follow-up after treatment was 5.5 (range:1-19) years. Two patients are alive with no evidence of disease for 7.5 and 10 years, one of whom was diagnosed with papillary thyroid carcinoma 9.5 years after treatment. One of the patients who died had lived for 19 years after diagnosis. CONCLUSIONS: Pineoblastomas are rare but very aggressive tumors; more effective treatment strategies are needed. Survivors should be followed up for late effects such as second malignancies and endocrine deficiencies.

Out-of-Hospital Emergencies in Children Under Palliative Home Care.

Introduction: Specialized palliative home care (SPHC) enables children and adolescents with life-limiting illnesses and complex needs to receive care at home. In addition to controlling symptoms and stabilizing the psychosocial situation, crisis anticipation is a component of SPHC. Since the establishment of the reporting SPHC team, parents have called for additional help from emergency medical services (EMS) in emergency situations with unexpected frequency. Children with life limiting diseases could undergo invasive procedures and unhelpful treatments with uncertain consequences. The questions arose as to which factors led to the involvement of the EMS in a palliative situation, what therapy was performed and what outcome could be reached. Methods: Records of the pediatric SPHC patients and EMS call-outs in these children of the reporting SPHC-team in the central region of Hesse, Germany (population: 1.1 million) were retrospectively analyzed from 01.11.2014 to 01.05.2021. The causes of the call-outs, the existence of an emergency agreement, the National Advisory Committee for Aeronautics (NACA) score, EMS therapy and outcome were examined. Patient data included age, palliative-justifying diagnosis, duration and intensity of care, place of death and median overall survival (MOS) and palliative SHPC treatment. Results: In total, 172 patients were analyzed during the study period. There were 27 EMS calls for a total of 20 patients/families (= EMS group). Palliative illness or a complication was the most frequent cause of call-outs. The patients in the EMS group were significantly less likely to have a DNR order, required more home visits and telephone calls and were under SPHC care for longer. There was a significantly higher proportion of crisis interventions at home visits. The children in the EMS group died less often from the underlying disease. Of the remaining 152 patients (= non-EMS group), a significantly higher proportion had a European home country. Conclusions: Despite the introduction of the SPHC, parents still call the EMS. Good cooperation and joint training should be sought to prepare all those involved for future call-outs.

Diarrhea in Placebo Arms of Cancer Studies.

Background/Aim: Diarrhea is among the most common adverse events in early oncology clinical trials, and drug causality may be difficult to determine. Materials and Methods: This is a systematic literature review of placebo arms of randomized cancer trials. Results: Anemia was reported in 95 of 127 placebo monotherapy cohorts. Publications involving healthy volunteers and cancer prevention studies reported lower frequencies than those with cancer patients. The average reported frequency of diarrhea grade 1 or higher among studies in cancer patients was 15%. The maximal reported frequencies for grades 1, 2, 3, 4, 5 were 56, 24, 6, 2, and 0%, respectively. Conclusion: When higher diarrhea frequencies than those are observed in treatment arms of clinical trials, then drug causality is likely.

Prolonged Response of a Patient with Relapsed Acute Myeloid Leukemia to a Novel Oral Bromodomain Extraterminal Inhibitor (BETi).

Acute myeloid leukemia (AML) is an aggressive clonal bone marrow cancer characterized by high rates of relapse and mortality. A middle-aged woman with AML relapsed twice after achieving complete remission with induction therapy and subsequent salvage therapy. She was then enrolled in a clinical trial with the bromodomain extraterminal inhibitor (BETi) mivebresib and achieved complete remission with incomplete count recovery (CRi) with monotherapy. Subsequently, she relapsed and was transitioned to combination therapy with mivebresib plus venetoclax and achieved CR again. The patient required eltrombopag to decrease platelet dependence in both arms of the trial and exhibited less myelosuppression with the combination therapy. The exceptional response to mivebresib demonstrated by this patient underscores the therapeutic potential of mivebresib.

Treatment of children under 4 years of age with medulloblastoma and ependymoma in the HIT2000/HIT-REZ 2005 trials: Neuropsychological outcome 5 years after treatment.

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors.

PURPOSE: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. PATIENTS AND METHODS: A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. RESULTS: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2-3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8-1.9). CONCLUSIONS: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.