Bexarotene and Erlotinib for Aerodigestive Tract Cancer

2005 ◽  
Vol 23 (34) ◽  
pp. 8757-8764 ◽  
Author(s):  
Konstantin H. Dragnev ◽  
W. Jeffrey Petty ◽  
Sumit Shah ◽  
Adrian Biddle ◽  
Neil B. Desai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cyclin D1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Aerodigestive Tract ◽  
Clinical Activity ◽  
Lung Carcinogenesis ◽  
Egfr Expression

Purpose The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. Patients and Methods In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non–small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. Results Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%. Conclusion The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.

The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3637-TPS3637 ◽  
Author(s):  
Andres Cervantes-Ruiperez ◽  
Ben Markman ◽  
Salvatore Siena ◽  
Carles Pericay ◽  
Giuseppe Aprile ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Tumor Biopsy ◽  
Egfr Expression ◽  
To Receive

TPS3637 Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are progression on 1L containing oxaliplatin, ECOG 0-1, and adequate hematological and liver function. Main exclusion criteria: prior anti-EGFR treatment. A total of 160 patients in 2L mCRC (stratified for EGFR expression, disease progression before or after 6 months after starting 1L, prior treatment with bevacizumab Y vs N) will be randomized to receive either GA201 (day 1, 8 of cycle 1 then q2W) or cet (qW) + FOLFIRI q2W (KRAS WT) or to receive GA201+ FOLFIRI or FOLFIRI alone (KRAS mutant). Collection of archival tumor plus a mandatory fresh tumor biopsy at baseline were implemented because ph I data showed that EGFR expression is not concordant between the two specimen types and to optimize assessment of potential immune related biomarkers. The fresh tumor biopsy will be centrally analyzed for EGFR (immunohistochemistry) and KRAS status. Primary objective is progression free survival; secondary endpoints are to define objective response rates, the safety profile, pharmacokinetics and pharmacodynamics. A comprehensive biomarker program (blood and tumor), mainly immune-phenotyping, immunohistochemistry in tumor samples (Ventana) and immune functional tests (including adaptive responses) were set up to investigate potential predictive biomarkers and the mode of action of GA201. Study is ongoing worldwide in 9 countries with the safety run-in phase completed in Nov 2011. Recruitment is planned to be completed by end of April 2012.

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

Insulin Growth Factor 1 Receptor (IGF-1R) Inhibitor, Linsitinib (OSI-906) in Combination with Bortezomib and Dexamethasone Demonstrates Favorable Safety Prolife and Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4234-4234
Author(s):  
Suzanne Trudel ◽  
Darrell White ◽  
Martin Gyger ◽  
Jonahtan Kaufmann ◽  
Andrzej Jakubowiak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Predictive Biomarkers ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Advisory Committees

Abstract Background: Preclinical studies have demonstrated anti-myeloma activity of IGF-1R inhibition against myeloma cell lines, primary patient samples and myeloma xenograft models. Further, it has previously been reported that IGF-1R inhibition enhances the in vitro activity of bortezomib (BTZ), suggesting that IGF-1R inhibitors may improve the clinical efficacy of proteosome inhibitors (PIs). Based upon these observations, we initiated a phase I trial combining linsitinib (a selective IGF-IR an IR inhibitor) with BTZ and dexamethasone (Dex) to clinically evaluate the tolerance and efficacy of this combination. Methods: This study investigates BTZ 1.3 mg/m2 and dex 20 mg given on days 1, 4, 8, and 11 together with escalating doses of oral linsitinib (75-150mg bid) given daily on a 21-day cycle. Continued daily linsitinib and BTZ dosing on days 1, 8, 15 and 22 of a 35-day cycle is allowed after 8 cycles for those benefitting and tolerating treatment. The primary objective is to determine the maximum tolerated dose (MTD) of the combination using a modified 3+3 design with 4 dose cohorts. The secondary objectives are to assess tolerability, pharmacokinetics (PKs), predictive biomarkers and clinical activity. Responses per dosing cohort are assessed by IMWG criteria (plus MRs as per the EBMT). Results: 18 patients (pts) have been enrolled to date into dose levels 75 mg (n=3), 100 mg (n=6), 125 mg (n=5) and 150 mg (n=4). All pts had refractory and/or progressive disease (PD); with a median number of 3 prior lines of treatment (range 1- 4). 67% of pts had received prior immunomodulatory drugs (IMiDs), 78% had prior PI exposure of which 3 were were confirmed refractory, and 50% had received both an IMiD and a PI. Two dose limiting toxicities (DLT) consisting of Gr 4 thrombocytopenia without bleeding (100 mg dose) and a grade 4 ALT (150 mg dose) were observed. All DLTs were reversible. The most common (>20%) adverse events (AEs) were anemia (41%), nausea (35%), fatigue (41%), creatinine increase (47%), thrombocytopenia (88%), cough (35%) and increase in ALT (24%). Most were grade 1-2. The most frequent Gr 3-4 AEs (>10%) regardless of causality were diarrhea (17.6%), back pain (11.8%), thrombocytopenia (47.1%), anemia (17.6%) and neutropenia (11.8%). Additional Gr 3 toxicities included renal insufficiency due to progressive disease (PD), pneumonia, altered mental state (not drug-related) and weight loss. Two deaths occurred; one due to PD, the other due to a cardiac event possibly related to BTZ. IGF-1R expression on CD138 positive cells was confirmed by flow cytometry in 8 pts. Analysis of substrate phosphorylation downstream of IGF-1R at baseline, are ongoing. PK analysis will also be reported. Of 18 pts assessable for response we observed 1 sCR, 1 VGPR, 7 PRs and 2 MR, for an overall response rate (ORR) of 50% and a clinical benefit rate of 61% (PR+MR). 5 pts achieved SD and 2 pts had PD. Of the 2 pts that had PD, neither expressed IGF-1R and of the 3 pts that were progressing on a PI-based regimen immediately prior to starting linistinib and BTZ, one achieved a PR, one an MR and one had SD. The median PFS is 7.3 months. Pts have received a median of 5 cycles of treatment (range 1-22). Dose escalation of linistinib at the 150 mg cohort is currently ongoing. Conclusions: The combination of BTZ and linsitinib is supported by preclinical rationale and has produced stable disease or better in 88% of advanced myeloma patients and appears to be safe and well tolerated. The optimal dose of linsitinib combined with BTZ however, has yet to be defined and data from the complete cohort of pts in addition to studies correlating response to tumor expression of IGF-1R and CD45 will be presented. Disclosures White: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Jakubowiak:SkylineDx: Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Onyx: Consultancy; Otsuka: Research Funding; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Janssen Ortho: Honoraria.

scholarly journals Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms

2018 ◽  
Vol 2 (24) ◽  
pp. 3572-3580 ◽  
Author(s):  
Raajit K. Rampal ◽  
John O. Mascarenhas ◽  
Heidi E. Kosiorek ◽  
Leah Price ◽  
Dmitriy Berenzon ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Myelofibrosis ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Combination Regimen ◽  
Blast Phase ◽  
Dismal Prognosis

Abstract Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m2 per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma

2008 ◽  
Vol 26 (36) ◽  
pp. 5950-5956 ◽  
Author(s):  
Jeffrey S. Weber ◽  
Steven O’Day ◽  
Walter Urba ◽  
John Powderly ◽  
Geoff Nichol ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Complete Response ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Multiple Doses ◽  
Group A ◽  
Group B

PurposeThe primary objective of this phase I/II study was to determine the safety and pharmacokinetic profile of either transfectoma- or a hybridoma-derived ipilimumab. Secondary objectives included determination of a maximum-tolerated dose and assessment of clinical activity.Patients and MethodsEighty-eight patients with unresectable stage III or IV melanoma with at least one measurable lesion were treated. Mean age was 59 years, with 65% male and 35% female patients, and 79% of patients had received prior systemic therapy. Single doses of ipilimumab up to 20 mg/kg (group A, single dose), multiple doses up to 5 mg/kg (group A, multiple dose), and multiple doses up to 10 mg/kg (group B) were administered.ResultsSingle dosing up to 20 mg/kg of transfectoma antibody was well tolerated, as were multiple doses up to 10 mg/kg without a maximum-tolerated dose. In group B, dose-limiting toxicity was seen in six of 23 melanoma patients. Grade 3 or 4 immune-related adverse events (irAEs) were observed in 14% of patients (12 of 88 patients), and grade 1 or 2 irAEs were seen in an additional 58%. The half-life of ipilimumab was 359 hours. In group B, there was one partial response (23+ months), one complete response (21+ months), and seven patients with stable disease (SD), for a disease control rate of 39%. Two patients in group B with SD had slow, steady decline in tumor burden that was ongoing at 1 year of observation.ConclusionIpilimumab has activity in patients with metastatic melanoma. Late responses were observed in patients with prolonged SD.

scholarly journals Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3211-3219 ◽  
Author(s):  
Shinichi Kitada ◽  
Christina L. Kress ◽  
Maryla Krajewska ◽  
Lee Jia ◽  
Maurizio Pellecchia ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
Parent Compound ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Low Grade ◽  
Altered Expression ◽  
Cell Counts

Abstract Altered expression of Bcl-2 family proteins plays central roles in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. In this study, we compared the toxicity and efficacy in mice of natural product gossypol and its semisynthetic derivative apo-gossypol, compounds that bind and inhibit antiapoptotic Bcl-2 family proteins. Daily oral dosing studies showed that mice tolerate doses of apogossypol 2- to 4-times higher than gossypol. Hepatotoxicity and gastrointestinal toxicity represented the major adverse activities of gossypol, with apogossypol far less toxic. Efficacy was tested in transgenic mice in which Bcl-2 is overexpressed in B cells, resembling low-grade follicular lymphoma in humans. In vitro, Bcl-2–expressing B cells from transgenic mice were more sensitive to cytotoxicity induced by apogossypol than gossypol, with LD50 values of 3 to 5 μM and 7.5 to 10 μM, respectively. In vivo, using the maximum tolerated dose of gossypol for sequential daily dosing, apogossypol displayed superior activity to gossypol in terms of reducing splenomegaly and reducing B-cell counts in spleens of Bcl-2–transgenic mice. Taken together, these studies indicate that apogossypol is superior to parent compound gossypol with respect to toxicology and efficacy, suggesting that further development of this compound for cancer therapy is warranted.

Biomarker analysis of phase (Ph) IB trial of radium-223 (Rad) and niraparib (Nira) in patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) (NiraRad).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5036-5036
Author(s):  
Eddy Shih-Hsin Yang ◽  
Benjamin Leiby ◽  
Guru P. Sonpavde ◽  
David Johnson Einstein ◽  
Zachary L. Quinn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Primary Objective ◽  
Exploratory Analysis ◽  
Clinical Activity ◽  
Radium 223 ◽  
Biomarker Analysis ◽  
Advanced Analysis ◽  
Immune Pathways ◽  
Parp 1

5036 Background: Rad is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC pts with bone metastases. PARP-1 activity critically supports androgen receptor (AR) activity in mCRPC and potentiates AR-dependent DNA damage response pathways that promote prostate cancer cell survival. Nira is a potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in mCRPC. We previously reported the safety of targeting the PARP-1/AR axis with Nira in combination with Rad. Herein we describe the results of an exploratory biomarker analysis. Methods: The primary objective of NiraRad is to determine the optimum Ph II dose of Nira plus Rad (55 kBq/kg of body weight IV every 4 weeks (wks) x 6) in pts with and without prior chemotherapy (docetaxel). Pts were enrolled to one of three dose levels of Nira (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 pts at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment (tx) duration > 18 wks, the median time on tx in the cohort of pts analyzed. A threshold of > 2 fold (X) differentially expressed genes was used. Results: Of the 23 pts with biomarker data, 7 (30%) experienced PSA reductions and 11 (48%) received tx for > 18 wks, 6 of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in pts who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p < 0.01) and C3D15 (4.8X, p < 0.001) in pts with tx duration > 18 wks and at baseline in pts who had PSA reductions (3.1X, p < 0.05). Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in pts with tx duration > 18 wks. Conclusions: Previously Nira and Rad have been shown to have acceptable tolerability in mCRPC pts. This exploratory analysis suggests potential response biomarkers that warrant further investigation. Managed by: the Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, Inc. Clinical trial information: NCT03076203.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

1996 ◽  
Vol 14 (12) ◽  
pp. 3074-3084 ◽  
Author(s):  
E K Rowinsky ◽  
S H Kaufmann ◽  
S D Baker ◽  
L B Grochow ◽  
T L Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
In Vitro Studies ◽  
Pharmacokinetic Studies ◽  
Sequence Dependence ◽  
Renal Tubular

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

1998 ◽  
Vol 16 (12) ◽  
pp. 3858-3865 ◽  
Author(s):  
L B Saltz ◽  
D Spriggs ◽  
L J Schaaf ◽  
G K Schwartz ◽  
D Ilson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Irinotecan Dose ◽  
Pharmacologic Study

PURPOSE In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

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