Final results of a phase I study of oral belinostat (PXD101) in patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3531-3531 ◽  
Author(s):  
W. K. Kelly ◽  
J. DeBono ◽  
G. Blumenschein ◽  
U. Lassen ◽  
J. Zain ◽  
...  
Keyword(s):  
Clinical Activity ◽  
Atypical Chest Pain ◽  
Dose Cohort ◽  
Multiple Tumor ◽  
Multiple Schedules ◽  
Deacetylase Inhibitor ◽  
Effect Of Food ◽  
Cancer Types ◽  
Elevated Creatinine ◽  
Tumor Types

3531 Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. IV Bel is well-tolerated with clinical activity at 1 g/m2 daily x5, q3w. Methods: Patients (pts) were treated with multiple schedules (see table) to assess safety, pharmacokinetics (PK) and efficacy. PK was done on day (d) 1 (fasting) and d7 (non-fasting) along with serial ECGs. Results: 92 pts, median age 60 (range 32–89) have been included. Major cancer types included colorectal (22%), prostate (17%), bladder (11%). Most frequent related adverse events (AEs), any grade (gr), were fatigue (53%), nausea (49%), anorexia (36%), vomiting (27%), diarrhea (25%). Only related gr 3/4 AE noted by more than 1 pt was fatigue. Hematological tox included gr 2: anemia (6 pts), leucopenia (2 pts), and thrombocytopenia (1 pt). Two events of gr 2 QTc prolongation were reported. Recommended dose (RD) for continuous dosing was determined as 250 mg, QD or BID, based on dose limiting toxicity (DLT; gr 3 if not indicated) seen in 2 pts in cohort 2A: dehydration and fatigue. Based on overall tolerability and DLTs (cohort 2C fatigue; 3C gr 2 nausea/vomiting/diarrhea; 4C atypical chest pain, elevated creatinine; 2D atrial fibrillation, hypokalemia, fatigue) the RD for d1–14 dosing was determined as 750 mg QD, with option for intra-pt dose escalation if limited tox. For d1–5 dosing, evaluation of the highest dose-cohort is not finalized; 1 pt had gr 3 psychosis, but also experienced same event 16d after treatment stopped. Exposure of Bel in plasma correlates with dose; PK on d1/d7 indicate a possible effect of food. To date, 33 pts (41%) have SD; 5 pts ≥6 months (d on treatment: 710 adenoidcystic, +488 bladder, 485 renal, 196 rectal, 182 prostate), and 12 pts 3–6 months. Conclusions: Oral Bel can be delivered safely with multiple schedules. The safety profile and long stabilizations in multiple tumor types makes Bel an interesting option for further evaluation as a monotherapy and in combination with chemotherapy. [Table: see text] [Table: see text]

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

Distribution of ETV6-NTRK3 translocations across neoplasms identified from the Mitelman Database.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23141-e23141
Author(s):  
Juan Carlos Malpartida ◽  
Eric Vick ◽  
Noah Hunter Richardson ◽  
Kruti Patel ◽  
Matthew K Stein ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Tumor Type ◽  
Invasive Adenocarcinoma ◽  
Data Set ◽  
Oncogenic Potential ◽  
Multiple Tumor ◽  
Cancer Types ◽  
Mitelman Database ◽  
Tumor Types ◽  
Tumor Profiling

e23141 Background: Discovered as a novel aberration in congenital fibrosarcoma (CF), the ETV6-NTRK3 translocation (EN) confers oncogenic potential and is inhibited by crizotinib. The present study aims to survey the scope of neoplasms that harbor EN across tumor types. Methods: Utilizing the National Cancer Institute’s Mitelman Database (MD) of Chromosome Aberrations and Gene Fusions patients (pts) were identified with EN and categorized based on tumor type, subtype and incidence. Cancer pts who received tumor profiling with Caris were also surveyed for EN. Results: 47 pts with EN across 12 cancer types were extracted from the MD and had median age of 0.17 years (7 unreported); 38% male; 51% acquired malignancies, 49% congenital; 62% cases were pediatric, 23% adult and 15% unknown. 0/204 pts with Caris tumor profiling were found to have an EN. Cancers with the highest number of EN were: 15 (31.9% EN data set) congenital mesoblastic nephromas (CMN), 10 (21.3%) CF, 7 (14.9%) breast carcinoma (BC; 6 secretory ductal carcinoma (SD) and 1 invasive adenocarcinoma (IA)) and 3 (6.4%) colorectal carcinoma (CRC). EN were found in 8 other malignancies (Table 1). Cancer types with the highest incidence of EN+ cases in the MD were gastrointestinal stromal tumor (GIST; 100%), CMN (75%) and CF (23.3%). Conclusions: These results further our understanding of the distribution of ETV6-NTRK3 translocations in multiple tumor types across the age spectrum and suggest that pts with CMN, CF, BC and CRC requiring high order therapy should be considered for NTRK3-based treatment. [Table: see text]

scholarly journals Structure and Optimization of Checkpoint Inhibitors

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 38 ◽  
Author(s):  
Sarah L. Picardo ◽  
Jeffrey Doi ◽  
Aaron R. Hansen
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Clinical Activity ◽  
Binding Affinities ◽  
Protein Targets ◽  
Dosing Regimens ◽  
Cancer Types ◽  
Tumor Types

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced (adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9093-9093 ◽  
Author(s):  
Jonathan Wade Goldman ◽  
Scott Joseph Antonia ◽  
Scott N. Gettinger ◽  
Hossein Borghaei ◽  
Julie R. Brahmer ◽  
...  
Keyword(s):  
Phase 1 ◽  
Clinical Activity ◽  
Multiple Tumor ◽  
Secondary Endpoints ◽  
Expression Activity ◽  
Grade 3 ◽  
Tumor Expression ◽  
Ecog Ps ◽  
Tumor Types

9093 Background: The fully human anti–PD-1 antibody N offers long-term OS benefit in patients (pts) with previously treated adv NSCLC. Adding I (anti–CTLA-4 antibody) to N has been shown to improve clinical activity vs either agent alone in multiple tumor types. We present long-term data for 1L N+I treatment of pts with adv NSCLC from CheckMate 012. Methods: In two cohorts in this phase 1 study, pts with recurrent stage IIIb/IV, chemotherapy-naive NSCLC and ECOG PS 0–1 received N 3 mg/kg Q2W combined with I 1 mg/kg Q12W (n=38) or Q6W (n=39) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and PFS. Exploratory endpoints included OS and efficacy by tumor PD-L1 expression. Results: In the N+I Q12W and N+I Q6W cohorts, respectively, 42% and 31% of pts experienced grade 3–4 treatment-related (TR) AEs; 18% in each cohort discontinued due to any-grade TRAEs. The most frequently reported any-grade TRAEs were pruritus (26%) and diarrhea (21%) with N+I Q12W, and fatigue (26%) and diarrhea (23%) with N+I Q6W. There were no TR deaths. N+I showed promising efficacy (table). While efficacy was enhanced with increasing PD-L1 expression, activity was noted in pts with <1% PD-L1 (table). Of 6 complete responses (CRs), 3 were in pts with <1% PD-L1. Conclusions: 1L therapy with N+I demonstrates a manageable safety profile and promising, durable efficacy (including pathological CRs) in adv NSCLC; efficacy was enhanced in pts with ≥1% PD-L1 tumor expression. Longer follow-up data, including 2-yr OS and characteristics of long-term survivors, will be presented. Clinical trial information: NCT01454102. [Table: see text]

Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): Update from a phase Ib study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9092-9092 ◽  
Author(s):  
Stephen V. Liu ◽  
D. Ross Camidge ◽  
Scott N. Gettinger ◽  
Giuseppe Giaccone ◽  
Rebecca Suk Heist ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Phase Iii ◽  
Clinical Activity ◽  
Multiple Tumor ◽  
Grade 5 ◽  
Platinum Based Chemotherapy ◽  
Potential Synergy ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Tumor Types

9092 Background: Platinum-based chemo is a standard first-line (1L) therapy for NSCLC lacking actionable gene alterations. Preclinical evidence suggests that chemo can play an immunomodulatory role and induce tumor antigen release, supporting combining chemo with immunotherapy. Atezo is a humanized and Fc-region-modified monoclonal anti-programmed death-ligand-1 (PD-L1) antibody that blocks interaction with PD1 or B7.1. The GP28328 study (NCT01633970) assessed safety and efficacy of atezo plus 1L chemo regimens in multiple tumor types. Methods: In this multicenter, multi-arm study, patients (pts) with locally advanced or metastatic NSCLC with no prior chemo for advanced disease received 15 mg/kg atezo IV q3w with standard doses of chemo (Arm C: carboplatin [carbo]+paclitaxel q3w; Arm D: carbo+pemetrexed q3w; Arm E: carbo+nab-paclitaxel qw) all for ≤6 cycles followed by atezo maintenance until loss of clinical benefit (+ pemetrexed maintenance until progression, Arm D). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), PFS, and OS. Results: By the 30 Aug 2016 cut-off, 76 NSCLC pts were evaluable (n = 25, 25, 26 for Arms C, D, E, respectively). At this cut-off, the most common treatment-related grade 3–4 adverse events (AEs) were neutropenia (36% C, 36% D, 42% E) and anemia (16% C, 16% D, 31% E). Three potentially related grade 5 AEs were seen (arm C: pneumonia; arm D: systemic candida; arm E: autoimmune hepatitis). Confirmed ORRs were 36%, 64%, 46% for Arms C, D (1 CR), and E (4 CR). Median PFS (95% CI) was 7.1 months (4.2–8.3) for C, 8.4 months (4.7–11) for D, and 5.7 months (4.4–14.8) for E. Median OS (95% CI) was 12.9 months (8.8–not evaluable) for C, 19.3 months (14.7–27.4) for D, and 14.8 months (12.7–not evaluable) for E. Conclusions: Atezo was well tolerated when combined with various chemo regimens for advanced NSCLC. Clinical activity in terms of ORR was favorable supporting potential synergy between atezo and chemo. PFS and OS data show promising benefits, but are limited by small numbers and wide confidence intervals. Phase III studies that include chemotherapy and atezolizumab are currently ongoing. Clinical trial information: NCT01633970.

Verification of the analytical performance of a molecular diagnostic for response to anti-PD1 therapy on the nCounter Dx Analysis System.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 8-8
Author(s):  
Brett Wallden ◽  
Irena Pekker ◽  
Simina Popa ◽  
Naeem Dowidar ◽  
Celine Ngouenet ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Cross Reactivity ◽  
Analytical Performance ◽  
Molecular Diagnostic ◽  
Clinical Activity ◽  
Gene Probe ◽  
Multiple Tumor ◽  
Input Range ◽  
Tumor Types

8 Background: Pembrolizumab is a humanized anti-PD1 antibody that is approved for use in advanced melanoma, recurrent or metastatic head and neck squamous cell carcinoma, and metastatic non-small-cell lung cancer. It has also shown clinical activity in a number of other tumor types in clinical trials, but there is need for a precise and accurate test that can identify patients most likely to benefit from therapy. We have previously described the development and analytical performance of a NanoString RNA expression clinical trial assay, referred to here as the Tumor Inflammation Signature (TIS) assay, which is being evaluated as a patient enrichment biomarker in multiple solid tumor types for treatment with pembrolizumab. Here we describe additional performance data and analytical verification of reproducibility from tissue and RNA input range in multiple tumor types. Methods: Linearity and specificity were assessed with single targets or pools of in vitro transcribed RNAs with sequences matching the 18 biomarker and 10 normalization gene probe targets. The verification of the previously reported analytical precision from RNA and reproducibility from tissue was performed using independent samples from 11 tumor types. The biological variability of the signature within a patient sample was evaluated by testing multiple core punches from formalin fixed paraffin embedded (FFPE) tissue blocks. Results: The TIS assay’s measurement of the 28 genes was linear across a wide dynamic range ( ≥ 4 logs) and was highly specific with < 1% cross reactivity between probes. The assay was verified across the specified RNA input range with > 90% concordance at the low end (50ng) of the RNA input range. The total standard deviation of the anti-PD1 Predictor Score from tissue was verified as < 5% of the signature score range and > 90% concordance in biomarker high/low categorization within the biological replicates. Conclusions: The analytical performance of the NanoString TIS assay was verified to be robust. The assay is well suited for decentralized clinical testing and is currently under investigation to identify responders to anti-PD1 therapy in multiple tumor types in several clinical studies.

scholarly journals In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs

2011 ◽  
Vol 3 (1_suppl) ◽  
pp. S37-S50 ◽  
Author(s):  
Neelesh Sharma ◽  
Alex A. Adjei
Keyword(s):  
Clinical Trials ◽  
Receptor Tyrosine Kinase ◽  
Clinical Activity ◽  
Protein Overexpression ◽  
Multiple Tumor ◽  
Patients With Cancer ◽  
Mesenchymal Epithelial Transition Factor ◽  
Tumor Types ◽  
Mesenchymal Epithelial Transition ◽  
Made In

The c-MET (mesenchymal–epithelial transition factor) pathway is dysregulated in many human cancers and promotes tumor growth, invasion and dissemination. The c-MET receptor tyrosine kinase can be activated via gene mutation, gene amplification, protein overexpression and/or a ligand-dependent autocrine/paracrine loop. Abnormalities in c-MET signaling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Significant progress has been made in advancement of c-MET pathway inhibitors through to clinical trials. A robust pipeline of high-quality inhibitors targeting different aspects of c-MET activation is currently being explored in phase I, II and III clinical trials across multiple tumor types. Preliminary data demonstrate promising clinical activity with these agents, along with an acceptable toxicity profile. In this manuscript, the pharmacological profile of drugs targeting the c-MET pathway and available data from ongoing clinical trials of these drugs are discussed.

Clinical activity and safety of the RET inhibitor pralsetinib in patients with RET fusion-positive solid tumors: Update from the ARROW trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3079-3079
Author(s):  
Vivek Subbiah ◽  
Philippe A. Cassier ◽  
Salvatore Siena ◽  
Guzman Alonso ◽  
Luis G. Paz-Ares ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Driver Mutations ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Tumor Type ◽  
Multiple Tumor ◽  
Duration Of Response ◽  
Tumor Types

3079 Background: RET fusions are targetable oncogenic drivers in multiple solid tumor types. ARROW study (NCT03037385) data supported the US FDA approval of pralsetinib, a once-daily (QD) oral highly potent and selective RET inhibitor, for RET-altered metastatic non-small cell lung cancer (NSCLC) and advanced/metastatic thyroid cancer. Here we provide an update on the clinical activity of pralsetinib in patients (pts) with advanced RET fusion-positive solid tumors other than NSCLC and thyroid cancer (“other” RET fusion–positive solid tumors). Methods: The global ongoing ARROW study (84 sites in 13 countries) includes phase 1 dose-escalation (30–600 mg [QD or twice daily]) and phase 2 expansion cohorts (400 mg QD) defined by tumor type and RET alteration status. Primary objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off) for 21 pts with other RET fusion–positive solid tumors enrolled by May 22, 2020 (enrollment cut-off) (lung other than NSCLC, n = 4; pancreatic, n = 3; colon, n = 3; cholangiocarcinoma, n = 3; unknown primary [UP], n = 2; other, n = 6). Overall, 11 (52%) pts received ≥2 prior lines of therapy for metastatic disease. The most common RET fusion partners were CCDC6 and KIF5B (24% each), NCOA4 (19%), other (10%), and unknown (24%). Two pts with colon cancer were excluded from efficacy analyses due to other driver mutations ( KRAS, PIK3CB). In 19 evaluable pts, ORR was 53% (95% CI, 29–76) with 2 (11%) complete responses (CR) and 8 (42%) partial responses (PR). Responses occurred across multiple tumor types including 3/3 pts with pancreatic cancer (including a CR ongoing at 20.8 months on treatment), 2/2 pts with UP, 2/3 pts with cholangiocarcinoma, and in pts with mesenchymal, salivary duct, and lung carcinoid tumors. Median duration of response was 19.0 months (95% CI, 5.5–not estimable). Clinical benefit rate (proportion with CR, PR, or stable disease persisting ≥16 weeks) was 68% (95% CI, 43–87). Tumor shrinkage was observed in 89% of 18 evaluable pts with post-baseline tumor assessment. In all pts enrolled in ARROW who received pralsetinib 400 mg QD irrespective of tumor type (n = 471) the most common (≥25%) treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (39%), anemia (35%), increased alanine aminotransferase (28%), constipation (26%), and hypertension (25%). Overall, 6% of pts discontinued treatment due to TRAEs. Conclusions: Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated. These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib. Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing. Clinical trial information: NCT03037385.

scholarly journals Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Megan M. Tu ◽  
Hany A. Abdel-Hafiz ◽  
Robert T. Jones ◽  
Annie Jean ◽  
Katelyn J. Hoff ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Response ◽  
Multiple Cancer ◽  
Cell Recruitment ◽  
Multiple Tumor ◽  
Area Of Interest ◽  
Signaling Axis ◽  
Metastasis Models ◽  
Cancer Types ◽  
Tumor Types

AbstractImmunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.

Phase I trial of vorinostat (V) in combination with pemetrexed (Pem) and cisplatin (CDDP) in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18088-18088 ◽  
Author(s):  
L. Chen ◽  
N. J. Vogelzang ◽  
G. Blumenschein ◽  
F. Robert ◽  
J. M. Pluda ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
First Line Therapy ◽  
Solid Malignancies ◽  
Deacetylase Inhibitor ◽  
Adequate Organ Function ◽  
Ecog Ps ◽  
Tumor Types

18088 Background: Pem and CDDP are active agents in many tumor types, and the combination is approved as first line therapy in malignant pleural mesothelioma (meso). Vorinostat (V), an orally active histone deacetylase inhibitor, was shown to induce PR in 2 meso patients (pts) (Krug 2006, Kelly 2005). A Phase I trial was undertaken to determine the safety and maximum tolerated dose (MTD) of Pem+CDDP+V. Methods: Pts with advanced solid malignancies, adequate organ function, ECOG PS = 2, = 1 prior chemotherapy, >18 yrs of age, and at least 6 months from prior treatment with Pem+CDDP were eligible. Patients were treated on 21 day cycles. V was started 2 days before standard doses of CDDP (75 mg/m2) and Pem (500 mg/m2) and was given on 4 schedules: dose levels were: I-200 mg BID for 14/21 d, II- 300 mg BID for 3/7 d wk1, 2 wk rest, III-300 mg QD for 7/21 d, and IV- 400 mg QD for 7/21 d. Results: Twenty-two pts were treated: median age was 60 (range 31–81); 13M: 9F. Tumor types were NSCLC 8, meso 5, bladder 3, colorectal 2, other 4. Nineteen of 22 patients were evaluable for investigator determined response: 1 CR (5.3%), 1 PR (5.3%), 11 SD (57.9%), 6 PD (31.6%). Conclusions: Dehydration and fatigue were common DLTs on different schedules of Pem+CDDP+V. V 300 mg x 7 days was tolerable in this combination. Hints of clinical activity were observed in bladder cancer and sarcoma patients, and stable disease was seen in three mesothelioma patients. Alternative dose schedules of Pem + V are under investigation. [Table: see text] No significant financial relationships to disclose.

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