Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in ...preclinical models and preliminary clinical studies to have activity against such tumors.
We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients.
A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia.
Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.
PLK1 is overexpressed in acute myeloid leukemia (AML). A phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients ...with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. A total of 44 R/R AML patients were treated with ONV + DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (
n
= 32). A 10-gene expression signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Twenty percent of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi), and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (
n
= 399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.
Abstract BACKGROUND Brain metastases are a common complication of cancer and also type of brain tumor: 10%-26% of patients develop brain metastases. Chemotherapy for these tumors is usually ...ineffective due to an intact blood-brain barrier (BBB). Anthracycline-sensitive cancers that metastasize to the brain do not receive anthracyclines which do not penetrate the brain. Triple-negative breast cancer (TNBC), which can be treated with doxorubicin (DOX) systemically has an incidence of brain metastases of approximately 25–46%; although lymphomas usually require an anthracycline as part of their chemotherapy, when they appear as a primary disease in the brain anthracyclines cannot be used. Berubicin is an analog of doxorubicin that appears to cross the BBB with significant central nervous system (CNS) uptake. A pivotal trial for patients with recurrent glioblastoma (GBM) after first-line therapy has finished enrollment with 252 patients in the US and Europe with evidence of efficacy and no impact on cardiac function. METHODS CNS Pharmaceuticals plans to evaluate Berubicin in patients with Primary CNS Lymphoma (PCNSL) who have never received an anthracycline and in TNBC with documented brain metastases. Patients will be enrolled if they have shown progression in the brain and have not undergone primary treatment. Outcome measurements will include efficacy in terms of overall response rates (ORR), progression-free survival (PFS), and overall survival (OS) as well as a continuing evaluation of Berubicin’s safety and tolerability. CONCLUSIONS The use of anthracyclines for the treatment of malignancy has encompassed 50 years of showing significant activity in certain diseases, however, use has been limited by both the risk of cardiotoxicity as well as the inability to penetrate the BBB, where these tumors tend to metastasize. This study offers the promise of using an anthracycline that can cross the BBB effectively for sensitive tumors and Berubicin becoming an important part of their therapy
Abstract
Background
Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system ...penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM.
Methods
GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140–220 mg/m2 every 3 weeks and BEV 10 mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria.
Results
Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200 mg/m2.
Conclusions
TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.
To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence ...of anticancer activity.
Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized.
Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d average: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL).
The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.
The purpose of our study was to assess the objective response to imatinib administered to patients with small cell lung cancer (SCLC).
Eligible patients were those with SCLC who either had ...chemotherapy-naive extensive-stage or had SCLC in a sensitive relapse. Patients enrolled on the trial were treated with 600 mg of imatinib daily. The response was assessed using Southwest Oncology Group (SWOG) criteria after 3 and 6 weeks. Tumor specimens were examined by immunohistochemistry for the KIT receptor.
Nineteen patients with SCLC entered on the study, including 16 men and 3 women. Nine patients had previously untreated extensive-stage disease and 10 patients had sensitive relapse. A central pathology review confirmed SCLC in only 14 of the 19 patients. There were no objective responses; however, one patient with sensitive-relapse disease had prolonged stabilization of disease (>3 months) while on imatinib therapy. The median time to progression was 0.8 months (range, 0.6-1.3 months) and 1.2 months (range, 0.2-4.1 months) in the previously untreated and sensitive-relapse groups, respectively. Tumor tissue samples from 4 (21%) of the 19 patients had the KIT receptor (CD117).
There was no observed antitumor activity in this limited Phase II trial of patients with SCLC, of which only a few tumors showed expression of the imatinib target. The results of this trial are, thus, inconclusive about the antitumor activity of imatinib against SCLC with the targeted KIT receptor (CD117). Further testing of imatinib in patients with SCLC will focus on demonstration of KIT expression in the setting of confirmed SCLC histology.
Abstract
Berubicin is an analog of doxorubicin (Dox) that appears to cross the BBB with significant central nervous system (CNS) uptake. RESULTS: of a Phase 1 dose-escalation study with 25 patients ...evaluable for efficacy showed 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%. Our current, potentially pivotal trial for patients with recurrent GBM after first-line therapy is enrolling in the US and Europe. It is unique in that all patients must be Grade 4 IDH WT, classifying these tumors as a poorer prognostic population than Grade 4 IDH mutated. Patients are randomized in a 2:1 design of Berubicin:Lomustine and stratified by MGMT methylation status. The primary endpoint is OS. Data has been presented showing that Berubicin and Lomustine arms are balanced with respect to MGMT status and demographics, with relatively comparable safety profiles (SNO Annual Meeting 2022 Abstract #383142). A pre-planned non-binding futlity analysis of the primary endpoint, OS, is being evaluated when the trial reaches ~30% of expected events (44 events). The interim analysis will be performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB). The futility analysis will be based on the conditional power that the trial will be positive (e.g., statistically significant difference between treatment groups’ OS). If the conditional power is <10% then the DSMB may recommend to end the study; otherwise the study will continue as it is currently planned. The review will also include safety and secondary efficacy endpoint summaries. RESULTS: of this interim analysis will be available for the SNO annual meeting and an evaluation of its outcome will be performed, with conclusions and recommendations for the further development of Berubicin as a therapeutic option for patients with recurrent GBM.
Abstract
Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with ...greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.
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