Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Population
2.2. Outcome
2.3. Potential Predictors
2.4. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
EUdraCT/NCT Trial Number: | Title | Population | Participants, n |
---|---|---|---|
NCT02058901 | High-dose protein kinase inhibitor | Solid tumors | 81 |
NCT02636426 | High-dose protein kinase inhibitor | Solid tumors | 18 |
2011–005116-28 | Cytotoxic drug in combination with radiopharmaceutical | Prostate cancer | 6 |
2014–000201-12 | Bispecific antibody (CEA antigen and CD3 T-cell) | CEA-expressing gastrointestinal adenocarcinomas | 4 |
2015–000673-12 | DNA-dependent protein kinase inhibitor | Solid tumors | 4 |
2011–002713-10 | Antibody-drug conjugate (anti-mesothelin—antimitotic agent) | Unresectable pancreatic cancer and platinum-resistant ovarian cancer | 5 |
2013–003041-41 | Targeted immunocytokine (CEA-IL2v) | Solid tumors | 11 |
2013–002663-25 | Vaccine (hVEGF26–104/RFASE) | Solid tumors | 25 |
NCT00989651 | A Phase I Study of Intravenous Carboplatin/Paclitaxel or Intravenous and Intraperitoneal Paclitaxel/Cisplatin in Combination with Continuous or Intermittent ABT-888 and Bevacizumab in Newly Diagnosed Patients with Previously Untreated Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer. | Epithelial ovarian, fallopian tube or primary peritoneal cancer. | 1 |
NCT01366144 | An Early Phase 1 Study of ABT-888 in Combination with Carboplatin and Paclitaxel in Patients with Hepatic or Renal Dysfunction and Solid Tumors. | Solid tumors | 1 |
NCT01351103 | A Phase I, open-label, dose escalation study of oral LGK974 in patients with malignancies dependent on Wnt ligands | Advanced solid tumors | 2 |
NCT01587703 | A Phase I/II Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects with NUT Midline Carcinoma (NMC) and Other Cancers | NUT midline carcinoma (NMC) and other cancers | 1 |
NCT01693562 | A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects With Advanced Solid Tumors. | Advanced solid tumors | 1 |
NCT01783171 | A Phase I Trial of Dinaciclib (SCH727965) and MK2206 in Metastatic Pancreatic Cancer with an Expansion Cohort in Advanced Pancreatic Cancer | Advanced and metastatic pancreatic cancer | 2 |
NCT01968109 | A Phase 1/2a Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination with Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors | Advanced solid tumors | 27 |
NCT02048384 | An Exploratory Study of Metformin With or Without Rapamycin as Maintenance Therapy After Induction Chemotherapy in Subjects with Metastatic Pancreatic Adenocarcinoma | Pancreatic cancer | 7 |
NCT01749397 | A Phase I Trial of the Combination of the PARP Inhibitor ABT-888 with Intraperitoneal Floxuridine (FUDR) in Epithelial Ovarian, Primary Peritoneal and Fallopian Tube Cancers | Epithelial ovarian, primary peritoneal and fallopian tube cancers | 2 |
NCT02073994 | A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects with Advanced Solid Tumors, Including Glioma, with an IDH1 Mutation. | Advanced solid tumors | 3 |
NCT02248805 | A Phase 1, First-in-Human, Open Label, Dose Escalation Study of MGD007, A Humanized gpA33 x CD3 Dual-Affinity Re-Targeting (DART®) Protein in Patients with Relapsed/Refractory Metastatic Colorectal Carcinoma | Advanced colorectal cancer | 10 |
NCT02000947 | A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of MEDI4736 in Combination with Tremelimumab in Subjects with Advanced Non-small Cell Lung Cancer. | Advanced non-small-cell lung cancer | 3 |
NCT02035358 | A Phase 1 Study of HyperAcute Renal (HAR) Immunotherapy In Patients with Metastatic Renal Cell Cancer | Advanced renal cell cancer | 1 |
NCT02501902 | An open-label phase IB study of Palbociclib (oral CDK 4/6 inhibitor) plus Abraxane (Nab-paclitaxel) in patients with metastatic pancreatic ductal adenocarcinoma | Advanced pancreatic cancer | 2 |
NCT02625857 | An Open-Label, Phase 1 Study of the Safety and Immunogenicity of JNJ-64041809, a Live Attenuated Listeria monocytogenes Immunotherapy, in Subjects with Metastatic Castration-resistant Prostate Cancer | Prostate cancer | 5 |
NCT02592967 | An Open-Label, Phase 1 Study of the Safety and Immunogenicity of JNJ-64041757, a Live Attenuated Listeria monocytogenes Immunotherapy, in Subjects With Non-Small Cell Lung Cancer | Non-small-cell lung cancer | 5 |
NCT02319018 | A Phase 1 Study of alisertib (MLN8237) in combination with mFOLFOX in gastrointestinal tumors | Gastrointestinal tumors | 4 |
NCT02514031 | Phase I/Ib, single-arm, open-label, multi-center trial using ARQ-761 (beta-lapachone) treatment with gemcitabine/nab-paclitaxel chemotherapy in metastatic, unresectable, or recurrent pancreatic cancer | Advanced pancreatic cancer | 6 |
NCT02766699 | A Phase 1 study to evaluate the safety, tolerability, and immunogenicity of EGFR (Vectibix® sequence)-targeted EDVs containing doxorubicin (EGFR(V)-EDV-Dox) in subjects with recurrent glioblastoma multiforme (GBM) | Recurrent glioblastoma | 6 |
NCT02716948 | A Pilot Study of Stereotactic Radiosurgery combined with Nivolumab in Patients with Newly Diagnosed Melanoma Metastases in the Brain and Spine | Melanoma | 4 |
NCT02588443 | Phase I study of neo-adjuvant RO7009789 alone or neo-adjuvant RO7009789 plus nab-paclitaxel and gemcitabine followed by adjuvant RO7009789 plus nab-paclitaxel and gemcitabine for patients with newly diagnosed resectable pancreatic carcinoma. | Pancreatic cancer | 3 |
NCT02453620 | A Phase 1 Study Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors | Advanced solid tumors | 12 |
NCT02572687 | An Open-Label, Multicenter, Phase 1 Study of Ramucriumab Plus MEDI4736 in Patients with Locally Advanced and Unresectable or Metastatic Gastrointestinal or Thoracic Malignancies | Advanced gastrointestinal or thoracic malignancies | 1 |
NCT01804530 | A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX7486-TsOH as a Single Agent and in Combination with Gemcitabine and nab-Paclitaxel in Patients with Advanced Solid Tumors. | Advanced solid tumors | 4 |
NCT02512172 | A study of using epigenetic modulators to enhance response to MK-3475 in microsatellite stable advanced colorectal cancer | Colorectal cancer | 16 |
NCT02491411 | A Pilot Study of Dexamethasone Therapy Prior to Rechallenge with Enzalutamide in Men with Metastatic Castration-Resistant Prostate Cancer Dex EXTends Enza Response (The DEXTER Trial) | Prostate cancer | 1 |
NCT02358473 | Open-label, Multicenter Phase 1 Study of Mogamulizumab (KW-0761) in Combination with Docetaxel in Previously Treated Subjects with Non-small Cell Lung Cancer (NSCLC) | Non-small-cell lung cancer | 1 |
NCT02355535 | Phase I Study of Procaspase Activating Compound-1 (PAC-1) in the Treatment of Advanced Malignancies | Advanced solid tumors | 7 |
NCT02262741 | A Phase 1 Study to Evaluate the Safety, Tolerability, and Efficacy of MEDI4736 in Combination with Tremelimumab in Subjects with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. | Advanced head and neck cancer | 1 |
NCT02619253 | A Phase I/Ib, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and Efficacy of Pembrolizumab (MK-3475) in Combination with Vorinostat in Patients with Advanced Renal or Urothelial Cell Carcinoma | Advanced renal or urothelial cell carcinoma | 11 |
NCT02890069 | Phase Ib, open-label, multi-center study to characterize the safety, tolerability and pharmacodynamics (PD) of PDR001 in combination with LCL161, everolimus (RAD001) or panobinostat | Advanced solid tumors | 10 |
NCT02631733 | A Phase I Study of a Combination of MM-398 and Veliparib in Solid Tumors | Advanced solid tumors | 2 |
NCT02833883 | A Phase 1b Study of Enzalutamide plus CC-115 in Men with Castration-Resistant Prostate Cancer (CRPC) | Prostate cancer | 5 |
NCT02989636 | Phase I Safety Study of Stereotactic Radiosurgery with Concurrent and Adjuvant PD-1 Antibody Nivolumab in Subjects with Recurrent or Metastatic Chordoma | Advanced chordoma | 3 |
NCT03043989 | Two independent phase 1b cohorts of docetaxel or cabazitaxel in combination with the potent CYP3A4 inhibitor, clarithromycin. | Prostate cancer | 4 |
NCT02655822 | A Phase 1/1b, Open-Label, Multicenter, Repeat-Dose, Dose-Selection Study of CPI-444 as Single Agent and in Combination with Atezolizumab in Patients with Selected Incurable Cancers | Advanced solid tumors | 14 |
NCT02819999 | A Study of Rovalpituzumab Tesirine (SC16LD6.5) in the Frontline Treatment of Patients with Extensive Stage Small Cell Lung Cancer | Small-cell lung cancer | 1 |
NCT02520778 | 9903 A Phase 1B Study of AZD9291 in Combination with Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor | Non-small-cell lung cancer | 1 |
NCT03051477 | A Phase I Dose Escalating Trial of Mistletoe Extract in Patients with Advanced Solid Tumors | Advanced solid tumors | 12 |
NCT02608125 | A Phase 1 Open-Label, Multicenter, Dose-Escalation Study of PRN1371, a FGFR1–4 Kinase Inhibitor, in Adult Patients with Advanced Solid Tumors, followed by an Expansion Cohort in Patients with FGFR1, 2, 3, or 4 Genetic Alterations | Advanced solid tumors | 2 |
NCT02722538 | A Phase 1b, Multicenter, Open Label Study Evaluating Safety, Tolerability and Preliminary Efficacy of GemRIS 225 mg in Subjects with Muscle-Invasive Transitional Cell Carcinoma of the Bladder | Bladder cancer | 1 |
NCT02903914 | Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the Arginase Inhibitor INCB001158 (formerly known as CB-1158) as a Single Agent and in Combination with Immune Checkpoint Therapy in Patients with Advanced/Metastatic Solid Tumors | Advanced solid tumors | 8 |
NCT03246074 | Phase I Clinical Trial of Combined Fostamatinib and Paclitaxel in Ovarian Cancer | Ovarian cancer | 3 |
NCT03148418 | An Open-Label, Multicenter Extension and Long-term Observational Study in Patients Previously Enrolled in a Genentech and/or F. Hoffman-La Roche LTD Sponsored Atezolizumab Study | Advanced solid tumors | 1 |
NCT3238027 | A Phase 1, Open-Label, Dose Escalation Trial to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of SNDX-6352 Monotherapy and SNDX-6352 in Combination with Durvalumab in Patients with Unresectable, Recurrent, Locally-Advanced, or Metastatic Solid Tumors | Advanced solid tumors | 10 |
NCT03219268 | A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD013, A Bispecific DART® Protein binding PD-1 and LAG-3 in Patients with Unresectable or Metastatic Neoplasms | Advanced solid tumors | 6 |
NCT03058289 | A Phase 1/2 Safety Study of Intratumorally Administered INT230–6 in Adult Subjects with Advanced Refractory Cancers | Advanced solid tumors | 2 |
NCT03299946 | Feasibility and Efficacy of Neoadjuvant Cabozantinib plus Nivolumab (CaboNivo) Followed by Definitive Resection for Patients with Locally Advanced Hepatocellular Carcinoma (HCC) | Hepatocellular carcinoma (HCC) | 3 |
NCT02675946 | A Phase 1 Open-label Dose Escalation and Dose Expansion Study of CGX1321 in Subjects with Advanced Solid Tumors and Phase 1b Study of CGX1321 in Combination with Pembrolizumab in Subjects with Advanced Gastrointestinal Tumors | Advanced gastrointestinal tumors | 3 |
NCT03257761 | A Phase Ib Study of Guadecitabine (SGI-110) and Durvalumab (MEDI 4736) in Patients with Advanced Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, and Cholangiocarcinoma/Gallbladder Cancer | Advanced hepatocellular carcinoma, pancreatic adenocarcinoma and cholangiocarcinoma/gallbladder cancer | 1 |
NCT02900664 | Phase Ib, open-label, multi-center study to characterize the safety, tolerability and pharmacodynamics (PD) of PDR001 in combination with CJM112, EGF816, Ilaris® (canakinumab) or Mekinist® (trametinib) | Advanced solid tumors | 1 |
2437136 | A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination with Pembrolizumab in Patients with Non-small Cell Lung Cancer, with Expansion Cohorts in Patients with Non-small Cell Lung Cancer, Melanoma and Mismatch Repair-Proficient Colorectal Cancer | Non-small-cell lung cancer, melanoma, mismatch repair-proficient colorectal cancer | 6 |
NCT03138538 | An Open-label, Phase I, Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects with Advanced Solid Tumors | Advanced solid tumors | 3 |
3137888 | Pilot study of spectroscopic MRI-guided, dose-escalated radiation therapy for newly-diagnosed glioblastoma | Glioblastoma | 1 |
NCT01849146 | Phase I Study of AZD1775 (adavosertib) with Radiation and Temozolomide in Patients with Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients with Recurrent Glioblastoma | Recurrent glioblastoma | 1 |
NCT02575794 | Phase 1 Dose Escalation and Drug Distribution Study of Oral Terameprocol in Patients with Recurrent High-Grade Glioma | High-grade glioma | 2 |
NCT02658981 | A Phase I Trial of Anti-LAG-3 or Anti-CD137 Alone and in Combination with Anti-PD-1 in Patients with Recurrent Glioblastoma | Recurrent glioblastoma | 3 |
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Characteristic | Statistics |
---|---|
Age, mean (SD) years | 61 (11) |
Sex, n (%) women | 204 (49) |
Recruited in the Netherlands, n (%) | 154 (37) |
Primary tumor, n (%) | |
Gastrointestinal | 207 (50) |
Genitourinary | 42 (10) |
Lung cancer | 32 (8) |
Skin and soft tissue cancer | 31 (7) |
Breast cancer | 28 (7) |
Gynecological | 19 (5) |
Head and neck | 18 (4) |
Glioblastoma | 17 (4) |
Neuroendocrine carcinoma | 8 (2) |
Others | 13 (3) |
ECOG/WHO performance status, n (%) a | |
0 | 118 (29) |
1 | 285 (69) |
>1 | 5 (1) |
BMI, mean (SD) (kg/m2) | 26 (5) |
BMI < 18.5, n (%) b | 20 (5) |
Opioid use, n (%) c | 177 (43) |
Three or more metastatic sites, n (%) | 118 (77) |
Any comorbidity other than primary malignancy, n (%) | 104 (25) |
Diabetes mellitus, n | 50 |
COPD, n | 20 |
Myocardial infarction, n | 12 |
Cerebrovascular accident or transient ischemic attack, n | 11 |
Peripheral vascular disease, n | 7 |
Liver disease, n | 7 |
Peptic ulcer disease, n | 7 |
Kidney disease, n | 7 |
Connective tissue disease, n | 6 |
Heart failure, n | 2 |
History of thromboembolism, n (%) d | 57 (14) |
Laboratory tests | |
Hemoglobin (mmol/L) < 7.45, n (%) | 221 (53) |
White blood cell count (109/L) > ULN, n (%) | 62 (15) |
Lymphocytes (109/L) < LLN, n (%) e | 70 (17) |
Neutrophils (109/L) > ULN, n (%) f | 56 (14) |
Neutrophils-to-lymphocytes (NTL) ratio > 5, n (%) g | 154 (38) |
Platelets (109/L) > 440, n (%) h | 30 (7) |
Sodium (mmol/l) < LLN, n (%) i | 28 (7) |
Creatinine clearance (ml/min/1.73 m2) < 60, n (%) j | 56 (14) |
Albumin (g/L) < 35, n (%) k | 125 (30) |
Lactate dehydrogenase (U/L) > 600, n (%) l | 34 (11) |
AST (U/L) > ULN, n (%) m | 132 (32) |
ALT (U/L) > ULN, n (%) n | 59 (14) |
Alkaline phosphatase (U/L) > 2.5 x ULN, n (%) o | 67 (16) |
Characteristic | n (%) |
---|---|
Early trial discontinuation | 82 (20) |
Reasons for early trial discontinuation (n = 82) a | |
Progressive disease | 36 (44) |
Physical deterioration (not otherwise specified) | 15 (18) |
Patient’s request | 10 (12) |
Toxicity (not dose limiting) | 10 (12) |
Dose-limiting toxicity or serious adverse event | 5 (6) |
Death | 4 (5) |
Protocol violation | 1 (1) |
90-day mortality b | 88 (22) |
Predictor | Univariable Analysis | Multivariable Analysis | ||
---|---|---|---|---|
OR (95%CI) | p | OR (95%CI) | p | |
ECOG/WHO performance status | ||||
1 vs. 0 | 2.98 (1.51–5.86) | <0.01 | 2.07 (1.03–4.19) | 0.04 |
BMI (kg/m2) | 0.96 (0.92–1.01) | 0.14 | ||
<18.5 vs. ≥18.5 | 2.92 (1.15–7.41) | 0.02 | ||
Use of opioids vs. non-use | 2.44 (1.48–4.01) | <0.01 | 1.82 (1.07–3.08) | 0.03 |
Metastatic sites | ||||
≥3 metastatic sites vs. <3 | 1.45 (0.89–2.35) | 0.14 | ||
Charlson Comorbidity Score | ||||
≥1 vs. 0 | 0.74 (0.41–1.33) | 0.31 | ||
History of thromboembolism | ||||
Yes vs. no | 1.23 (0.63–2.42) | 0.54 | ||
Laboratory tests | ||||
Hemoglobin (mmol/L) < 7.45 | 1.58 (0.96–2.59) | 0.07 | ||
White blood cell count (109/L) > ULN | 1.67 (0.90–3.11) | 0.10 | ||
Lymphocytes (109/L) < LLN | 1.12 (0.60–2.10) | 0.73 | ||
Neutrophils (109/L) > ULN | 2.20 (1.18–4.11) | 0.01 | ||
Neutrophils-to-lymphocytes (NTL) ratio > 5 | 1.52 (0.93–2.49) | 0.09 | ||
Platelets (109/L) > 440 | 2.55 (1.16–5.60) | 0.02 | ||
Sodium (mmol/L) < LLN | 4.04 (1.84–8.88) | <0.01 | 2.95 (1.27–6.84) | 0.01 |
Creatinine clearance (mL/min/1.73 m2) < 60 | 1.00 (0.49–2.03) | 1.00 | ||
Albumin (g/L) < 35 | 2.56 (1.55–4.23) | <0.01 | ||
Lactate dehydrogenase (U/L) > 600 | 2.25 (1.03–4.93) | 0.04 | ||
AST (U/L) > ULN | 2.22 (1.34–3.68) | <0.01 | ||
ALT (U/L) > ULN | 1.33 (0.69–2.57) | 0.39 | ||
Alkaline phosphatase (U/L) > 2.5 × ULN | 3.36 (1.90–5.93) | <0.01 | 2.72 (1.49–4.99) | 0.001 |
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Douma, J.A.J.; Buffart, L.M.; Sedhom, R.; Labots, M.; Menke-van der Houven van Oordt, W.C.; Skardhamar, M.; De Felice, A.; Lee, E.; Dharmaraj, D.; Azad, N.S.; et al. Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology. Cancers 2021, 13, 2304. https://doi.org/10.3390/cancers13102304
Douma JAJ, Buffart LM, Sedhom R, Labots M, Menke-van der Houven van Oordt WC, Skardhamar M, De Felice A, Lee E, Dharmaraj D, Azad NS, et al. Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology. Cancers. 2021; 13(10):2304. https://doi.org/10.3390/cancers13102304
Chicago/Turabian StyleDouma, Joeri A. J., Laurien M. Buffart, Ramy Sedhom, Mariette Labots, Willemien C. Menke-van der Houven van Oordt, Mikkjal Skardhamar, Anthony De Felice, Esther Lee, Divya Dharmaraj, Nilofer S. Azad, and et al. 2021. "Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology" Cancers 13, no. 10: 2304. https://doi.org/10.3390/cancers13102304