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1. Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment

Author

Boosman, R.J., Boosman, R.J., Dorlo, T.P.C., de Rouw, N., Burgers, J.A., Dingemans, A.M.C., van den Heuvel, M.M., Hendriks, L.E.L., Biesma, B., Aerts, J.G.J.V., Croes, S., Mathijssen, R.H.J., Huitema, A.D.R., Ter Heine, R., Boosman, R.J., Boosman, R.J., Dorlo, T.P.C., de Rouw, N., Burgers, J.A., Dingemans, A.M.C., van den Heuvel, M.M., Hendriks, L.E.L., Biesma, B., Aerts, J.G.J.V., Croes, S., Mathijssen, R.H.J., Huitema, A.D.R., and Ter Heine, R.

Abstract

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m(2) would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Published
2021

2. Toxicity of pemetrexed during renal impairment explained : Implications for safe treatment

Author

Nikki de Rouw, Sander Croes, Anne-Marie C. Dingemans, Alwin D. R. Huitema, Ron H.J. Mathijssen, Michel M van den Heuvel, Joachim G.J.V. Aerts, Lizza E.L. Hendriks, Thomas P.C. Dorlo, Rob ter Heine, Jacobus A. Burgers, Bonne Biesma, Rene J. Boosman, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Pulmonologie, MUMC+: MA Med Staf Spec Longziekten (9), RS: CAPHRI - R5 - Optimising Patient Care, MUMC+: DA KFT Medische Staf (9), Pulmonary Medicine, and Medical Oncology

Subjects
Male, Cancer Research, Lung Neoplasms, estimated glomerular filtration rate, Phases of clinical research, CONTINUAL REASSESSMENT METHOD, Carcinoma, Non-Small-Cell Lung, Tissue Distribution, pemetrexed, Aged, 80 and over, education.field_of_study, Clinical Trials, Phase I as Topic, INHIBITOR, Middle Aged, Prognosis, CANCER, Pemetrexed, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Toxicity, ACID, Female, medicine.drug, Adult, medicine.medical_specialty, Population, PHASE-I EVALUATION, Urology, Renal function, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Clinical Trials, Phase II as Topic, Therapeutic index, SDG 3 - Good Health and Well-being, LY231514, NEUTROPENIA, medicine, Humans, MULTITARGETED ANTIFOLATE, Dosing, education, Contraindication, non-small cell lung cancer, Aged, prophylactic strategies, Dose-Response Relationship, Drug, business.industry, MODEL, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Dietary Supplements, Folic Acid Antagonists, Kidney Failure, Chronic, business, Follow-Up Studies
Abstract

Contains fulltext : 238572.pdf (Publisher’s version ) (Closed access) Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]

Published
2021

3. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation.

Author

Rinaldi, David A., Kuhn, John G., Burris, Howard A., Dorr, F. Andrew, Rodriguez, Gladys, Eckhardt, S. Gail, Jones, Suzanne, Woodworth, James R., Baker, Sharyn, Langley, Connie, Mascorro, David, Abrahams, Trent, and Von Hoff, Daniel D.

Abstract

Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m2. The MTD of MTA was 600 mg/m2, with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m2 dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m2, 266 μg · h/ml, and 7.0 l/m2, respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m2. MTA is a promising new anticancer agent. [ABSTRACT FROM AUTHOR]

Published
1999
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4. Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay.

Author

Britten, Carolyn D., Izbicka, Elzbieta, Hilsenbeck, Susan, Lawrence, Richard, Davidson, Karen, Cerna, Caeser, Gomez, Lionel, Rowinsky, Eric K., Weitman, Steven, and Von Hoff, Daniel D.

Abstract

Purpose: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. Materials and methods: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 μg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. Results: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 μg/ml, 11% (17/148) at 1.0 μg/ml, and 23% (33/141) at 10 μg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 μg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. Conclusions: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant. [ABSTRACT FROM AUTHOR]

Published
1999
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5. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer

Author

William J. John, Cesare Gridelli, Jesus Corral, Michael Thomas, Filippo de Marinis, Paolo Bidoli, Nadia Chouaki, Carla Visseren-Grul, Jean-Louis Pujol, Annamaria Zimmermann, Belen San Antonio, Mircea Dediu, Luis Paz-Ares, Pujol, J, Paz-Ares, L, de Marinis, F, Dediu, M, Thomas, M, Bidoli, P, Corral, J, San Antonio, B, Chouaki, N, John, W, Zimmermann, A, Visseren-Grul, C, and Gridelli, C

Subjects
Male, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Guanine, Lung Neoplasms, Pemetrexed, Placebo, Maintenance Chemotherapy, Glutamates, LY231514, Quality of life, Maintenance therapy, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, ALIMTA, medicine, Humans, Post-induction maintenance therapy, Paramount, Lung cancer, Adverse effect, Neoplasm Staging, business.industry, Anemia, Nausea, Common Terminology Criteria for Adverse Events, Induction Chemotherapy, Middle Aged, medicine.disease, Survival Analysis, Surgery, Treatment Outcome, Withholding Treatment, Disease Progression, Quality of Life, NS-NSCLC, Low-grade toxicities, Cisplatin, business, Progressive disease, medicine.drug
Abstract

IntroductionIn the PARAMOUNT (“A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non–Small-Cell Lung Cancer”) trial, patients with advanced nonsquamous non–small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL.Materials and MethodsPatients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m2, day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed.ResultsA median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms.ConclusionPARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.

Published
2014

6. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck

Author

Xavier Pivot, B Laguerre, L. Cals, M. Schneider, L. Kayitalire, V Ripoche, J L Lefebvre, Eric Raymond, D Gedouin, J Latz, M Degardin, J.P. Armand, C. Niyikiza, and R Johnson

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Guanine, Neutropenia, medicine.medical_treatment, Antineoplastic Agents, Pemetrexed, head and neck squamous cell carcinoma, chemotherapy, Gastroenterology, chemistry.chemical_compound, LY231514, Glutamates, Internal medicine, medicine, Mucositis, Humans, Enzyme Inhibitors, pemetrexed disodium, Aged, Chemotherapy, multitargeted antifolate, business.industry, Remission Induction, Regular Article, ALIMTA®, Middle Aged, medicine.disease, Thrombocytopenia, Surgery, Oncology, chemistry, Epidermoid carcinoma, Head and Neck Neoplasms, Antifolate, Carcinoma, Squamous Cell, Folic Acid Antagonists, Female, Neoplasm Recurrence, Local, business, Febrile neutropenia, Progressive disease, medicine.drug
Abstract

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m2 administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9–20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7–28.1 months; 95% CI: 3.9–7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B12 supplementation. © 2001 Cancer Research Campaign http://www.bjcancer.com

Published
2001

7. Dipyridamole potentiates the in vitro activity of MTA (LY231514) by inhibition of thymidine transport

Author

Nicola J. Curtin, David R. Newell, P G Smith, and E Marshman

Subjects
Cancer Research, Guanine, Population, dipyridamole, Pemetrexed, Thymidylate synthase, chemistry.chemical_compound, Glutamates, LY231514, Tumor Cells, Cultured, Humans, Enzyme Inhibitors, education, hypoxanthine transport, Hypoxanthine, thymidine transport, education.field_of_study, biology, Chemistry, Hypoxanthine transport, Biological Transport, Drug Synergism, Regular Article, Thymidylate Synthase, Transport inhibitor, Molecular biology, Oncology, Biochemistry, biology.protein, Growth inhibition, Thymidine, Nucleoside
Abstract

The novel pyrrolopyrimidine-based antifolate LY231514 (MTA), inhibits multiple folate-requiring enzymes including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Both thymidine and hypoxanthine are required to reverse MTA growth inhibition in leukaemia and colon cancer cells. Prevention of MTA growth inhibition by thymidine and/or hypoxanthine was investigated in two human lung (A549, COR L23) and two breast (MCF7, T47D) tumour cell lines, and the effect of the nucleoside/base transport inhibitor dipyridamole (DP) on thymidine and hypoxanthine rescue defined. MTA IC50values (continuous exposure three population doublings) were: A549–640 n M, COR L23–28 n M, MCF7–52 n M and T47D–46 n M. Thymidine (1 μM) completely prevented growth inhibition at the MTA IC50in all cell lines. At 10 × IC50, growth inhibition was only partially reversed by thymidine (≤ 10 μM); both thymidine and hypoxanthine (30 μM) being required for complete reversal, reflecting the multi-targeted nature of MTA. Growth inhibition by MTA was not affected by hypoxanthine alone. A non-toxic concentration (1 μM) of DP prevented thymidine/hypoxanthine rescue of MTA indicating that DP may potentiate MTA activity by preventing nucleoside and/or base salvage. Thymidine transport was inhibited by ≥ 89% by 1 μM DP in all cell lines, whereas hypoxanthine transport was inhibited only in A549 and MCF7 cells. Therefore, prevention of end-product reversal of MTA-induced growth inhibition by DP can be explained by inhibition of thymidine transport alone. © 2000 Cancer Research Campaign

Published
2000

8. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

Author

Pujol JL, Paz-Ares L, de Marinis F, Dediu M, Thomas M, Bidoli P, Corral J, San Antonio B, Chouaki N, John W, Zimmermann A, Visseren-Grul C, and Gridelli C

Subjects
Anemia etiology, Carcinoma, Non-Small-Cell Lung mortality, Cisplatin administration & dosage, Cisplatin adverse effects, Disease Progression, Glutamates adverse effects, Guanine administration & dosage, Guanine adverse effects, Humans, Induction Chemotherapy, Lung Neoplasms mortality, Male, Middle Aged, Nausea etiology, Neoplasm Staging, Pemetrexed, Quality of Life, Survival Analysis, Treatment Outcome, Withholding Treatment, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Glutamates administration & dosage, Guanine analogs & derivatives, Lung Neoplasms drug therapy, Maintenance Chemotherapy
Abstract

Introduction: In the PARAMOUNT ("A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL., Materials and Methods: Patients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m(2), day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed., Results: A median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms., Conclusion: PARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2014
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