Dose-limiting Toxicity Assessment Period Research Articles

A phase 2 study of fruquintinib in combination with S-1 for second-line treatment of esophageal squamous cell carcinoma after first-line immunotherapy failure.

323 Background: Patients with advanced esophageal squamous carcinoma (ESCC) who experience progression after first-line immunotherapy face a challenging treatment landscape. The potential of anti-vascular therapy combined with chemotherapy in the treatment of esophageal cancer is well-established. Mechanistically, anti-angiogenic agents can promote the normalization of tumor vasculature and facilitate the access of chemotherapeutic agents to tumor targets. Considering the compromised physical condition of advanced ESCC patients, there is a preference for more convenient oral medications. Therefore, we conducted this phase II study to assess the clinical efficacy and safety of combining fruquintinib with S-1 in treating advanced ESCC patients following first-line immunotherapy failure. Methods: This open-label, single-arm, phase II study consists of dose-finding and dose-expansion phases, enrolling advanced or metastatic ESCC patients after first-line immunotherapy failure. The dose-finding phase followed a 3+3 design. Patients received fruquintinib (3mg, 4mg, 5mg, d1-d14, q3w, respectively), in combination with S-1 (40mg, 50mg, 60mg, bid, d1-d14, q3w, based on body surface area (BSA)), until unacceptable toxicities, progressive disease, or death. The initial fruquintinib dose was 4 mg d1-d14, q3w, in combination with an appropriate S-1 dose. Additional patients were enrolled in the dose-expansion phase and received the maximum tolerated dose determined in the dose-finding phase. Results: As of August 1, 2023, seven patients were enrolled in the dose-finding phase. One patient withdrew consent during the DLT assessment period. Among the patients administered a 4mg dose of fruquintinib, one out of three achieved a confirmed partial response (PR) after 7 cycles of treatment. Additionally, two out of three patients at the 5mg dose level achieved PR after 2 cycles of treatment, resulting in an overall response rate (ORR) of 50% (3/6). The disease control rate (DCR) was 100% (6/6). The median progression-free survival (PFS) was observed to be 4.93 months (95% CI: 1.93 – 10.73), with overall survival (OS) at 10.73 months (95% CI: 2.1 – 10.73). In terms of safety, no dose-limiting toxicities (DLTs) were reported at 4mg dose level. While DLTs were observed in two out of the three patients at the 5mg dose level. The most common treatment-related adverse events (TRAE) across all grades were fatigue (5/7) and extremity pain (4/7). Grade 3 TRAE were identified in 5 patients, with hypertension (2/7), mucositis (2/7), and fatigue (2/7) being reported. No grade 4 or higher TRAEs were observed. Conclusions: Potential benefits were demonstrated when using fruquintinib in combination with S-1 for the treatment of ESCC patients after immunotherapy failure. The efficacy and safety of fruquintinib and S-1 will be further investigated in this trial later. Clinical trial information: NCT05636150 .

Abstract A018: Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study

Abstract Mitazalimab is a human CD40 agonistic IgG1antibody being developed as cancer immunotherapy. Targeting CD40 kickstarts the cancer immunity cycle by licensing DCs leading to tumor-specific T cell priming and activation. Furthermore, in PDAC, CD40 agonism activates myeloid cells and promotes the degradation of the desmoplastic tumor stroma, improving the influx of T cells and chemotherapeutic agents into the tumor. Mitazalimab has shown to be safe and well tolerated (at doses up to 1200 μg/kg) with signs of clinical activity in solid tumors in a Phase I study (NCT02829099). Most drug related adverse events (AE) were grade 1 or 2. OPTIMIZE-1 (NCT04888312) is a phase 1b/2, open-label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX in adults diagnosed with previously untreated mPDAC. The objective of the first (phase 1b) part of the study was to determine the RP2D of mitazalimab + mFOLFIRINOX. Mitazalimab was escalated from 450 µg/kg to 900 µg/kg following a Bayesian optimal interval design with at least 3 patients enrolled per dose level. In the first 21-day treatment cycle (Dose Limiting Toxicity assessment period), mitazalimab is administered intravenously on day 1 and 10 and mFOLFIRINOX starts on day 8. In the second and subsequent cycles, treatment follows a 14-day cycle schedule where mitazalimab is administered 2 days after mFOLFIRINOX. In part 2 of the study (phase 2), mitazalimab at the RP2D will be administered in combination with mFOLFIRINOX. Primary endpoint is RECIST-defined overall response rate. Progression-free survival and overall survival will be assessed as secondary endpoints. We report data from phase 1b (dose escalation) part of this study. As of March 9, 2022, 11 patients were treated with mitazalimab: 5 at 450 µg/kg and 6 at 900 µg/kg mitazalimab doses. One patient in the 900 µg/kg dose cohort withdrew from the trial for administrative reasons after the first mitazalimab infusion, prior to receiving mFOLFIRINOX and was not included in RP2D determination. Key baseline characteristics included: 7 female, 4 male; median age 63 (range 57-70); ECOG 0-1; median time since mPDAC diagnosis, 25 days. Mitazalimab related AEs were reported in 9/11 patients. Treatment related AEs occurring in >1 patient were fever (60%), muscle pain (50%) and fatigue (20%). At the 450 µg/kg dose, all mitazalimab related AEs were grade 1-2. At the 900 µg/kg dose, 4 patients (67%) experienced grade 1-2 mitazalimab related AEs. One patient in the 900 µg/kg dose experienced mitazalimab related grade 3 fatigue and grade 3 headache that led to treatment discontinuation after the first cycle. There were no mitazalimab related grade 4 or 5 AEs. 1/10 patients required mFOLFIRINOX dose reduction and, at the cutoff date, the range of treatment length was 1-14 weeks. Mitazalimab combined with mFOLFIRINOX is safe and well tolerated. The 900 µg/kg dose of mitazalimab was selected as the RP2D. Phase 2 of the OPTIMIZE-1 trial is currently enrolling patients. Citation Format: Jean-Luc Van Laethem, Ivan Borbath, Hans Prenen, Aurélien Lambert, Karen Geboes, Jean-Frédéric Blanc, Yago Pico de Coaña, Karin Enell-Smith, Lena Schultz, Karin Nordbladh, Peter Ellmark, Sumeet Ambarkhane, Malin Carlsson, Philippe Cassier. Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A018.

Combination of nivolumab with chemoradiotherapy for locally advanced cervical cancer: NiCOL phase I trial.

5534 Background: Current management of locally-advanced cervical cancers (LACC) relies on chemoradiotherapy (CRT) and brachytherapy. The causal relation between cervical cancer and human papillomavirus infection, which engenders tumor expression of immunoreactive neo-antigens, together with high PD-L1 expression, warrants consideration of immune checkpoint inhibitors (ICI) in the definitive treatment of this disease. We assessed the safety of concurrent and maintenance nivolumab in addition to CRT in patients with LACC. Methods: This prospective, multi-center, dose-confirmation, phase I clinical trial (NiCOL trial; NCT03298893) evaluated the tolerance profile of concurrent and maintenance nivolumab in addition to CRT (45 Gy in 25 fractions with cisplatin 40mg/m² q1w, followed by a brachytherapy boost to 85 Gy) for stage IB3-IVA cervical cancers. Nivolumab was administered at 240 mg q2w starting on day 1 of CRT and in maintenance after CRT completion for up to 6 months (13 cycles). The primary endpoint was the incidence of dose-limiting toxicities (DLT) within 11 weeks after the initiation of treatment (defining the DLT assessment period), corresponding to the first 6 cycles of nivolumab. DLT were defined as grade ≥3 non-hematological toxicities, grade ≥3 immune-related adverse event (irAE), persistent grade ≥2 irAE for ≥1 week despite optimal supportive care, or ≥1-week radiotherapy delay related to treatment toxicity. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and treatment tolerance profile. Results: 16 patients (pts) were recruited between 11/2017 and 07/2020. Median age was 46 years [range: 27-77]. Histological types were squamous cell carcinomas (n = 14) and adenocarcinomas (n = 2). Tumors were staged as FIGO IB3 (n = 2), IIB (n = 8), IIIB (n = 1), IIIC1 (n = 4) and IVA (n = 1); 13 tumors were HPV-positive. Three patients experienced DLT, corresponding to grade 3 hypotension (n = 2) and grade 3 acute kidney injury (n = 1). Following the DLT assessment period, while receiving maintenance nivolumab, one patient developed a grade ≥3 irAE corresponding to a grade 3 diarrhea. Two months after brachytherapy completion, ORR was 93.8% [95%CI: 69.8%-99.8%]. With a median follow-up of 16.6 months, three patients experienced disease control failure (at 3,4 and 5 months); site of disease progression was local for two patients, and simultaneously local and distant for one patient. One-year PFS was 81.2% [95% CI: 64.2%-100%]. Conclusions: Concomitant nivolumab with definitive CRT, followed by maintenance nivolumab, appears to be a safe and feasible therapeutic option for LACC, associated with encouraging PFS rates. Further trials evaluating ICI combined with CRT for LACC are warranted in light of these promising results and of those from recent studies evaluating ICI in the metastatic setting. Clinical trial information: NCT03298893.

Abstract P5-17-08: A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC)

Abstract Background C-C Chemokine Ligand type-5 (CCR5) is overexpressed in >95% of TNBC and has been correlated with disease progression. Moreover, enhancement of DNA repair signaling by CCR5 activation may contribute to chemotherapy resistance. Therefore, blocking CCR5 may result in increased immune response against tumor cells and synergize with chemotherapy. Leronlimab (PRO 140) is a humanized monoclonal antibody to CCR5. Preclinical data showed leronlimab binds human CCR5, blocks CCR5-mediated signaling, and CCL5-induced breast cancer cell invasion. The therapeutic antibody leronlimab has been administered to over 800 healthy and HIV-1 infected individuals with good tolerance and without obvious dose-related toxicity, making it an ideal partner for chemotherapy combinations in TNBC. Methods In this ongoing phase 1B/2 study, patients with CCR5+ mTNBC with ≤2 line of therapy in the metastatic setting (no prior carboplatin) are treated with weekly subcutaneous leronlimab (3 dose levels, 3+3 dose escalation) and a fixed dose of carboplatin AUC 5 on day 1 with a 21-day dose-limiting toxicity (DLT) window, followed by expansion in 30 patients with CCR5+ mTNBC who are naïve to chemotherapy in the metastatic setting or who have failed first-line combination of chemotherapy (excluding carboplatin) and a checkpoint inhibitor in the metastatic setting. CCR5 positivity is centrally assessed by IHC and defined as >10% CCR5 staining in primary or metastatic tumor cells and/or high predominance of CCR5+ tumor-infiltrating leukocytes (TIL). Primary objectives are safety, tolerability, determination of maximum tolerated dose, and determination of the recommended phase 2 dose (RP2D). Results Fifteen patients had archived tumor tissue assessed for CCR5 expression, with 12 being CCR5 positive (median expression 20%, range 0 - 100%, and 7 out of 12 high CCR5+ TILs) . A total of ten patients (median age 51 years; median 2 prior therapies) have been enrolled at 3 dose levels (350, 525, and 700 mg). In the second cohort, 1 additional patient was inadvertently enrolled. All patients completed the DLT assessment period and no DLTs have been observed. Patients received between 3 and 27 doses of leronlimab with the number of cycles ranging from 1 to 9. Five patients remain on treatment. The most common treatment-emergent adverse events (TEAEs) by any grade were: fatigue (6/10), headache (4/10), constipation (3/10), and nausea (3/10). The following grade ≥3 TEAEs were reported: neutropenia, anemia, thrombocytopenia, hyponatremia, hypertension, diarrhea and headache. Serious Adverse Events were reported in 2 patients (grade 2 sepsis and grade 3 headache). The following leronlimab treatment related adverse events (TRAEs) occurred (all grade 1): injection site reaction in cohort 1, fatigue (n=2) and headache in cohort 2. Three carboplatin TRAEs ≥3 were reported in one patient in cohort 1: thrombocytopenia, anemia and leukopenia. Two out of seven patients eligible for response achieved a confirmed partial response, and 4 patients stable disease. Conclusions Leronlimab, in combination with carboplatin, has been well-tolerated in all 3 dose levels with early signs of anti-tumor activity in patients with CCR5+ mTNBC. The study is currently enrolling patients at the RP2D dose of leronlimab 700mg in combination with carboplatin AUC 5 in the phase 2 part of the trial. Clinical trial information: NCT03838367 Citation Format: Massimo Cristofanilli, Namita Chittoria, Sima Ehsani, Hallgeir Rui, Milana Dolezal, Lisette Stork-Sloots, Femke de Snoo, Christopher Recknor, Vandana Abramson. A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-08.

Abstract CT015: A phase 1 dose escalation study of TB-403 in pediatric relapsed or refractory medulloblastoma, neuroblastoma, Ewing sarcoma, or alveolar rhabdomyosarcoma

Abstract Background: TB-403 is a monoclonal antibody directed against placental growth factor (PlGF). In medulloblastoma (MB), PlGF promotes tumor progression by activating downstream pathways that promote cell proliferation, cell survival and metastasis. Elevation in PlGF expression, or its receptor neuropilin 1 (Nrp1), is found in tumor samples in a variety of small round blue cell tumors, including MB, neuroblastoma (NB), Ewing sarcoma (ES), and alveolar rhabdomyosarcoma (ARMS). Additionally, pre-clinical studies have shown that TB-403 inhibits primary tumor growth and spinal metastasis in mice with orthotopic MB grafts, and that mice treated with TB-403 survive significantly longer than untreated animals. PlGF is expressed across human MB subtypes, and high expression of the PlGF receptor Nrp1 correlates with poor overall survival. Objective: Evaluate the safety and maximum tolerated dose (MTD) of TB-403 administered as a single agent during cycle 1 of therapy in children with relapsed or refractory MB, NB, ES or ARMS and measure pharmacokinetics (PK). Methods: A phase 1, open-label, multicenter, dose escalation study of TB-403 in pediatric subjects with relapsed or refractory MB, NB, ES or ARMS. The study involved 4 dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3+3 dose escalation scheme. A treatment cycle was 28 days. Subjects received 2 doses of TB-403 (on Days 1 and 15) per cycle unless they experienced toxicity. After cycle 1, temozolomide or etoposide could be added at the investigator's discretion. The primary objective was to determine the MTD of TB-403 monotherapy during a dose-limiting toxicity (DLT) assessment period or 1 cycle. The secondary and exploratory objectives included PK and plasma biomarkers respectively of TB-403 administered as a single agent or in combination with chemotherapy. For subjects who continued TB-403 treatment after the DLT assessment period, we evaluated preliminary efficacy. Results: Fifteen subjects enrolled; 3 to DL1 (Dose Level 1), 3 to DL2, 6 to DL3 and 3 to DL4. All subjects received 2 doses of TB-403 in cycle 1. Five serious treatment emergent adverse events were reported in 3 patients. None of these were considered serious unexpected adverse drug reactions. Conclusion: TB-403 was shown to be safe at all dose levels evaluated without reaching a MTD in pediatric subjects. Initial results look encouraging for incurable relapsed disease. Citation Format: Giselle L. Saulnier Sholler, Dan G. Duda, Genevieve Bergendahl, David Ebb, Matija Snuderl, Theodore W. Laetsch, Jennifer Michlitsch, Derek Hanson, Michael Isakoff, Kevin Bielamowicz, Jacquline Kraveka, Peter Carmeliet, Andy De Deene, Rakesh K. Jain. A phase 1 dose escalation study of TB-403 in pediatric relapsed or refractory medulloblastoma, neuroblastoma, Ewing sarcoma, or alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT015.

A phase I/II trial of trifluridine/tipiracil in combination with irinotecan in patients with advanced gastric cancer refractory to fluoropyrimidine, platinum, and taxane.

210 Background: Trifluridine/tipiracil (FTD/TPI) or irinotecan is a treatment option in the heavily pretreated patients with advanced gastric cancer (AGC) with the limited efficacy. Thus, we investigated the recommended dose of trifluridine/tipiracil (FTD/TPI) and irinotecan for these patients. Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used a escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on Days 1 and 15 of a 28-day schedule] with 2 dosage schedules of FTD/TPI:35 mg/m2/dose, twice daily (bid), on days 1-5 and 8-12 of a 28-day cycle (Level A) or on days 1-5 and days 15-19 of a 28-day cycle (Level B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) for phase I part and the evaluation of disease control rate (DCR) targeting > 55% in all enrolled patients for phase II part. Results: Eleven patients were enrolled from 4 institutions in Japan; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A (Grade 3 gum infection and Grade 3 febrile neutropenia on Day 29, outside the 28-day DLT assessment period, determined equivalent to DLT), and 2/6 patients at Level 2B (Grade 3 mucositis oral and Grade 3 febrile neutropenia). Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively. Conclusions: The RP2D was determined to be Level 1B although further investigation to explore optimal regimen is needed. Clinical trial information: UMIN000031346.

Phase II, open-label, randomized study of first-line zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in Claudin 18.2–positive metastatic pancreatic cancer (mPC).

TPS4667 Background: Combinations of folinic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) along with GN are standard first-line treatment options for mPC. Despite treatment advances, mPC has a poor prognosis with a 5-year survival rate of < 5%, emphasizing an urgent need for new targeted therapeutics. Claudin 18.2 (CLDN18.2) is a tight junction protein restricted to normal gastric mucosa cells; however, in the context of malignant transformation, CLDN18.2 is frequently expressed in carcinomas derived from organs that do not normally express it, such as pancreatic adenocarcinoma (50-70% express CLDN18.2). Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2, designed to mediate cancer cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Methods: This phase 2 study (NCT03816163) with a safety lead-in phase will assess safety and antitumor activity of zolbetuximab plus GN in patients (pts) with histologically confirmed mPC with high CLDN18.2 expression (≥75% of tumor cells demonstrate moderate-to-strong IHC staining). The safety lead-in will assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W then expand/de-escalate using a 3+3 design) plus GN and confirm the recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs), defined as a specified toxicity that occurs during the DLT assessment period and is related to zolbetuximab, will be assessed after Cycle 1 (28 days). After determining the RP2D, approximately 129 pts will be randomly assigned 2:1 to receive either zolbetuximab RP2D Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle ( Arm 1), or GN alone on Days 1, 8, and 15 of each cycle ( Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). Imaging (CT/MRI) will be performed at baseline and every 8 weeks until investigator-assessed disease progression (per RECIST v1.1 criteria) or the start of other systemic anticancer treatment, whichever comes earlier. Primary objectives are to confirm RP2D (safety lead-in), to assess antitumor activity measured by overall survival (randomization phase), and to establish the safety/tolerability profile of zolbetuximab plus GN across the study. Key secondary endpoints in the randomization phase are progression-free survival and objective response rate. As of January 2020, this study is recruiting pts at 74 centers. Clinical trial information: NCT03816163 .

Safety and tolerability of intratumorally administered OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: A phase I dose escalation clinical study.

3139 Background: There have been limited reports concerning treatment outcomes of oncolytic viruses in solid tumors other than melanoma. OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express GM-CSF to enhance tumor-specific immune responses. Methods: We conducted an open-label, single-center, phase 1 study. Eligible pts were 18-75 years of age; had histologically confirmed advanced solid tumor; had progressed after standard systemic treatments. Pts were required to have tumor(s) deemed safe to inject, with a longest diameter of at least 0.5cm. Other eligibility criteria included measurable lesion as per RECIST v1.1; ECOGPS score of 0-1 and adequate organ functions. A 3+3 dose-escalation strategy was used in the study and 3 dose levels (106, 107 and 108 CCID50/mL) of OH2 were assessed. OH2 was administered intratumorally every 3 weeks for the first cycle and every 2 weeks.Treatment may continue afterwards in ptswith potential clinical benefit at the discretion of the investigators. The primary objective was the safety and tolerability of OH2 injection as defined by the dose limiting toxicities (DLTs) within the first 3 weeks of therapy, and the maximum tolerated dose (MTD). Secondary objectives included efficacy and immunogenicity of OH2. Results: 11 pts were enrolled between April 17, 2019 and November 4, 2019. The median follow-up duration was 8.36 months (95%CI: 5.64-11.08). OH2 was well-tolerated as no DLTs were reported and no MTD reached. Before the end of the DLT assessment period,1 pt withdrew consent, and 1 pt died of arrhythmia unrelated to OH2, with negative OH2 DNA copies in serum, urine and saliva samples. Most treatment-related adverse events (TRAEs) observed were of grade 1-2, except that 1 pt in the 108 CCID50/mL group developed grade 3 fever. The most common TRAEs were fever (n =5) and blood bilirubin level increase (n = 4). There were no grade 4 or 5 TRAEs. One pt(rectal cancer) had PR and 2 (appendix cancer and ovarian cancer) had SD as per RECIST v1.1. One patient (esophageal cancer) achieved iPR as per iRECIST criteria. The duration of follow-up for the 2 responders were 9.70 months and 8.36 months, respectively, and both had ongoing responses. Notably, regression of a non-injected lesion was observed in 1 patient. Conclusions: OH2 had a favorable safety profile with no DLTs and MTD. The dose expansion study in selected tumor types is currently underway. Clinical trial information: NCT03866525 .

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies

SummaryBackground Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3–6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders.

Daily intravenous arsenic trioxide administered with all-trans retinoid acid, the standard-of-care for acute promyelocytic leukemia, is costly and challenging to administer. ORH-2014 is a novel, oral arsenic trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 dose-escalating study in patients with advanced hematologic malignancies. Twelve patients received ORH-2014 at 5 mg (n=3), 10 mg (n=6), or 15 mg (n=3) orally once a day (fasted state). Objectives were to assess the safety, tolerability and pharmacokinetics of ORH-2014 to support a dose recommendation for future trials. The median age of the patients was 77 years (range: 45-81) and they had received a median of two (range: 1-5) prior therapies. There were no dose limiting toxicities and no drug-related severe adverse events, except one grade III QT prolongation occurring beyond the dose limiting toxicity assessment period and resolving after treatment interruption. ORH-2014 steady-state plasma concentration was reached on day 15. ORH-2014, 15 mg Cmax was comparable to the calculated approved dose of intravenous arsenic trioxide (mean [% coefficient of variation]: 114 [21%] vs. 124 [60%] ng/mL) and area under the curve from 0 to 24 hours was 2,140 (36%) versus 1,302 (30%) h*ng/mL. These results indicate that ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxide at the approved dose (0.15 mg/kg); this ORH-2014 dose is recommended for future trials. (NCT03048344; www.clin-icaltrials.gov).

Phase 1 Study of Erlotinib and Metformin in Metastatic Triple-Negative Breast Cancer

BackgroundEpidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple-negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC. Patients and MethodsPatients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3 + 3 design. Dose-limiting toxicities (DLT) were assessed during the first 5 weeks of therapy. The primary objective was to determine the maximum tolerated dose of metformin with fixed-dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression-free survival. ResultsEight patients were enrolled. The median number of prior therapies for metastatic disease was 2.5 (range, 1-6). No DLT events were reported during the DLT assessment period. Most adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 adverse events were reported. The best observed response was stable disease in 2 patients (25%). Median progression-free survival was 60 days (range, 36-61 days). ConclusionErlotinib and metformin were well tolerated in a population of pretreated mTNBC patients but did not demonstrate efficacy in this population.

The phase Ib result of the safety and efficacy of lenvatinib (lenv) plus eribulin (eri) in advanced adipocytic sarcoma (LPS) and leiomyosarcoma (LMS): LEADER study (NCT03526679).

e22524 Background: Eri, although approved for advanced LPS, has limited activity in terms of tumor shrinkage. Anti-angiogenic agents have shown to increase tumor response in certain cancer types. This study aims to understand the safety, optimal dose, and efficacy of the combination of lenv, a multi-kinase anti-angiogenic inhibitor, and eri in LMS and LPS. Methods: Advanced LMS and LPS with no more than 2 lines of systemic chemotherapy were eligible. The starting dose was lenv 18mg/day daily and eri 1.1mg/m2 D1, D8 in a 21-day cycle. The primary endpoint of the phase Ib part was to assess the dose-limiting toxicity (DLT) in the first 21 days and to determine the recommended phase II dose (RP2D). A rule-based (≤ 33% DLT in first 6 pts) design was implemented in the phase Ib part. Results: From 2018 Jul 24 to 2019 Jan 8, a total of 6 pts (4 LMS, 1 dedifferentiated LPS, 1 myxoid LPS) were enrolled. The median age was 56 (range 30-70), female: male 3:3. Only 1 pt had a DLT, which was < 75% of the planned dosage. Within all (27) cycles, common grade (gr) 3 or higher adverse events (AE) included hypertension (HTN, n = 4), hand-foot syndrome (HFS, n = 3), and neutropenia (n = 4). However, 4 pts had late-onset gr3 or multiple coexisting gr2 AEs that necessitated dose reduction(s) (dr) for lenv (7 dr) or eri (2 dr) after the DLT assessment period (see table). The median time to 14 mg/day, 10mg/day of lenv, and eri 0.7mg/m2 was 22, 28 (after starting lenv 14mg/day), and 69 days, respectively. In terms of preliminary anti-tumor activity, 5 (83%) pts had target lesion shrinkage and 2 (33%) reached PR (1 confirmed) as best response according to RECIST 1.1. Conclusions: Late-onset AEs after cycle 1 leading to dose reduction was notable for lenv + eri and the RP2D was thus determined at a lower starting dose of lenv 14mg/day and eri 1.1mg/m2. The preliminary tumor response was also promising. Efficacy and safety of lenv + eri for LMS and LPS will continue to be explored in phase II study. Clinical trial information: NCT03526679. [Table: see text]

Abstract P6-18-35: A phase 1 study of erlotinib and metformin in advanced triple negative breast cancer

Abstract Background: The epidermal growth factor receptor (EGFR) is frequently overexpressed in triple negative breast cancer (TNBC). However, EGFR inhibitors have not shown efficacy as monotherapy in TNBC. One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. Metformin is a LKB1-dependent AMPK activator that inhibits both MAPK and AKT signaling. The combination of the EGFR inhibitor erlotinib and metformin synergistically induces apoptosis in TNBC cell lines and decreases tumor burden in PTEN-null EGFR-amplified mouse xenograft models. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with advanced TNBC. Methods: Patients with advanced TNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150mg daily. Metformin dose escalation was planned according to a 3+3 design, beginning at 850mg BID and escalating to 850mg TID. One de-escalation to 500mg BID was allowed. Dose-limiting toxicities (DLT) were assessed during the first five weeks of therapy. The primary objectives were to determine the maximum tolerated dose (MTD) of metformin with fixed dose erlotinib and to determine the potential for clinical benefit. Secondary endpoints were response rate, stable disease rate, and progression free survival. Pre- and on-treatment skin biopsies were collected to determine the effect of the study drugs on their respective cell signaling targets, particularly EGFR, AMPK, and mTOR. Results: Between March 2013 and May 2015, nine patients were screened and eight were enrolled. Median age was 48 years (range 37-79). Median number of prior therapies for metastatic disease was 2.5 (range 1-6). No DLT events were reported in either of the dose escalation cohorts during the DLT assessment period. AEs occurring in three or more patients and all grade III AEs are reported in Table 1. Grade III diarrhea despite maximum supportive care required dose reduction of metformin from 850mg TID to 850mg BID in one patient. Grade III rash led to study withdrawal in one patient. No grade IV AEs were reported. Per RECIST v1.1, the best observed response was stable disease in two patients (25%). Median time on study was 2.0 months (range 1.2-3.0). Skin biopsy marker assessment is ongoing and will be reported. Conclusion: The combination of erlotinib and metformin was generally well tolerated in a population of pre-treated metastatic TNBC patients. No unexpected toxicities occurred. While no responses were achieved, stable disease was observed in patients who received this non-chemotherapy combination. Adverse EventsEventMetformin 850mg BID n=3Metformin 850mg TID n=5All patients n=8 Number of patients (percent) All gradesGrade IIIAll gradesGrade IIIAll gradesGrade IIIRash3 (100)1 (33.3)5 (100)08 (100)1 (12.5)Diarrhea3 (100)05 (100)2 (40.0)8 (100)2 (25.0)Weight loss1 (33.3)05 (100)06 (75.0)0Dry skin1 (33.3)05 (100)06 (75.0)0Nausea2 (66.7)03 (60.0)05 (62.5)0Vomiting1 (33.3)03 (60.0)04 (50.0)0Dry mouth1 (33.3)03 (60.0)04 (50.0)0Dysgeusia1 (33.3)02 (40.0)03 (37.5)0Increased creatinine2 (66.7)01 (20.0)03 (37.5)0Fatigue1 (33.3)02 (40.0)03 (37.5)0Anorexia1 (33.3)02 (40.0)03 (37.5)0Hyponatremia1 (33.3)1 (33.3)001 (12.5)1 (12.5) Citation Format: Fenn KM, Maurer MA, Lee SM, Crew KD, Trivedi MS, Accordino MK, Hershman DL, Kalinsky K. A phase 1 study of erlotinib and metformin in advanced triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-35.

Randomized, Double-Blind Phase Ib/III Study of Erlotinib With Ramucirumab or Placebo in Previously Untreated EGFR-Mutant Metastatic Non–Small-Cell Lung Cancer (RELAY): Phase Ib Results

BackgroundDespite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non–small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC. Patients and MethodsEligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles. ResultsFourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment. ConclusionRamucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.

Exposure Adjusted Continuous Reassessment Method (EACRM) - an Adaptive Design Incorporating Time to Toxicity Event for Phase I Dose Finding Studies.

Finding the maximum tolerated dose (MTD) is the most important primary objective for Phase I oncology studies. The drug exposure and the toxicity event are the two components required for characterization of the MTD. Phase I trials currently require multiple subjects treated at numerous dose levels, with many of these subjects receiving doses of drug at less than predicted efficacious exposures. Further, these studies employ predefined, step-wise increments in doses that can result in inaccurate predictions of the MTD. Improvements to conventional adaptive dose finding designs to attain more accurate information on the extent of exposure and the time to event, with a more dynamic enrollment to facility better decision making are needed and have been the focus of previous published efforts. The EACRM dynamically extends the conventional adaptive dose finding designs by incorporating dose limiting toxicity (DLT) events as well as at-the-event information from each patient. An Accelerated Failure Time model with some tweaking to update the time to DLT for subjects who did not complete the entire DLT assessment period at particular time point was developed. Simulations, under a variety of assumptions, have indicated that the EACRM performed equal or better than the traditional 3+3 design in identifying the MTD and also outperformed the 3+3 design in other important operating characteristics such as the length of study, the number of subjects treated at above the MTD, and the total number of subjects.

Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey

IntroductionIt is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents. MethodsA 15-question survey was sent to corresponding authors of phase 1 reports. Questions involved: duration of the DLT assessment period, incorporation of specific grade 1 (G1) or G2 toxicity and their minimum duration to qualify as DLT, exclusion of specific G3 and inclusion of dose modification/delay. ResultsAmong the 400 investigators contacted, 93 replied of whom 65 completed the questionnaires. A total of 87% opted for an extended DLT assessment period beyond cycle 1, with the proviso not to delay patient accrual. Reanalysis at the end of the study of all safety data was proposed in order to recommend the phase 2 dose. Most respondents (92%) suggested including dose modification in the definition of DLT when dose intensity was decreased to 70%. Whilst moderate toxicity was deemed relevant by 70%, the G1/2 toxicities selected to define DLT however varied. ConclusionThe majority of experts favoured a longer DLT assessment period as well as incorporation of specific G2 toxicities into the DLT definition. However, no clear consensus existed on a re-definition of DLT. Therefore analyses of a large international data warehouse were also used to develop guidelines presented in a companion paper.

A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors

The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFRα and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors. Patients were enrolled into five dose-escalating cohorts of 3-6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1-3) or once every other week at 15 or 20 mg/kg (cohorts 4-5), with 4 weeks/cycle. Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 μg/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3-8.7)]. Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.

Abstract B153: A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamic (PD) activity of the dual PI3K/mTOR inhibitor GDC-0980 administered once weekly (QW).

Abstract Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 is a potent, selective, oral inhibitor of class I PI3K and mTOR kinase demonstrating broad activity in xenograft cancer models (breast, ovarian, lung, and prostate). Methods: A Phase I dose escalation study using a 3+3 design has been initiated in patients (pts) with advanced solid tumors or non-Hodgkin's lymphoma. GDC-0980 is administered QW. The objectives are to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD), evaluate PK and PD effects, and describe observed anti-tumor activity of GDC-0980 on this schedule. PD assessments include evaluating pAKT levels in platelet-rich plasma (PRP), biomarker pS6 in paired pre- and on-treatment tumor biopsies, tumor FDG avidity via PET imaging (FDG-PET), and tumor vasculature changes via DCE-MRI. Archival tumor tissue is evaluated for PTEN expression and PIK3CA mutations. Results: Thirty-two pts have been enrolled in 7 successive cohorts evaluating 6 to 200 mg of GDC-0980 QW. Drug-related adverse events (AEs) reported in ≥10% of pts were nausea, diarrhea, hyperglycemia, vomiting, and fatigue. The only Grade (g) ≥3 drug-related AEs have been g3 hyperglycemia at ≥150 mg GDC-0980. Hyperglycemic events have been asymptomatic and generally well managed after initiation of an oral diabetic agent. One patient each at 150 and 200 mg GDC-0980 experienced the DLT of a repeat fasting g3 hyperglycemia following a subsequent dose of GDC-0980 during the DLT assessment period despite initiation of oral diabetic therapy. The patient with the DLT at 150 mg has continued on-treatment for more than 8 months with isolated g3 events. Analyses of PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Levels of pAKT in PRP were inversely correlated with GDC-0980 plasma concentrations. All patients treated at ≥25 mg with evaluable-paired tumor biopsies demonstrated significant decreases in pS6 IHC staining of up to 100%. Signs of clinical activity include 3 pts [gastrointestinal stromal tumor (GIST), solitary fibrous tumor, and ovarian cancer] treated at 150 mg QW who are all currently on study after 7 months. Clinical and PD activity was also observed in a pt with epithelioid sarcoma who was treated at 25 mg QW for 11 mo with a 22% decrease in tumor FDG avidity and a pt with ovarian cancer who was treated at 100 mg for 6.2 months and demonstrated a 22% decrease in tumor lesions by RECIST and 48% decrease in serum CA-125. By DCE-MRI, the pt with GIST on 150 mg QW demonstrated a 60% decrease in the blood-normalized area under the signal intensity-time curve (AUCBN) in liver lesions as assessed by DCE-MRI after 2 doses of GDC-0980 suggesting a potential anti-angiogenic effect. Conclusions: GDC-0980 is generally well tolerated when administered QW up to 200 mg with signs of anti-tumor activity. Decreases in the PD markers pAKT and pS6 are consistent with downstream modulation of the PI3K pathway. Dose-escalation continues and updated PK/PD data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B153.

Abstract 1690: Definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents

Abstract Introduction: There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA). Methods: We retrieved all phase I trials testing monotherapy with an MTA published in English after January 1st, 2000. In each trial, all items used to define DLTs were recorded. Results: Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The median DLT assessment period was 28 days [range: 7-56]. Among the 155 trials, the most common category of hematologic toxicity was “hematologic toxicity, not otherwise specified (NOS)”. Similarly, the most common category of non-hematologic toxicity was “non-hematologic toxicity, NOS”. A total of 8 other categories of hematological items and 46 categories of non-hematologic organ-specific items were employed to define DLTs in the 155 trials reviewed. Organ-specific items were reported in 111 trials (72%). Mean number of organ-specific items per trial increased from 2.03 in the 2000-2005 timeframe to 2.79 in the 2006-2010 timeframe (p=0.02). The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE grading system. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. A number of other factors were increasingly found to influence the determination of DLT. Specifications about minimum duration and degree of reversibility were incorporated into the definition of a non-hematologic DLT in 13% and 12% of trials respectively. The need to delay treatment and to reduce dose-intensity because of toxicity was incorporated in the definition of DLT in 19% and 8% of trials respectively. The definition of DLT varied with administration schedule, with (near-)continuous dosing regimen often defining DLTs at lower severities. Definition of DLT did not differ according to classes of agents, to first-in-human versus not first-in-human studies or to dose escalation method used. Twenty three percent of the organ-specific DLTs defined in the trials in which non-hematologic DLTs occurred were actually encountered, suggesting an added value of these organ-specific DLTs to the generic definition. In 28 of the 155 trials (18%), toxicities were eventually considered to be DLTs even though they were not initially defined as such. Conversely, in 13 of the 155 trials (8%), toxicities were not reported as DLTs even though they were initially defined as such. Conclusions: The definition of DLT is heterogeneous across phase I cancer clinical trials of MTA administered as monotherapy and depended on the drug administration schedule. While our results do no support the standardization of the definition of DLT, we provide recommendations aiming at reducing the heterogeneity observed in the definition of DLT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2011-1690

Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: A review of the literature

AimThere is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA). MethodsWe retrieved all phase I trials testing monotherapy with an MTA published over the last decade. In each trial, all items used to define DLTs were recorded. ResultsReports of 155 phase I trials evaluating 111 different MTAs were reviewed. The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE classification. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. Specifications about minimum duration of toxicity, degree of reversibility, the need to delay treatment and to reduce dose-intensity because of toxicity were infrequently incorporated in the definition of DLT. The definition of DLT varied with administration schedule. Discrepancies between the initial and the final definition of DLT were reported in 25% of trials. ConclusionsWhile our results do not support a standardisation of the definition of DLT, the inclusion of following specifications in its definition when relevant would reduce the heterogeneity observed across trials: (1) DLT assessment period, (2) absolute severity according to NCI CTCAE classification as well as severity relative to baseline status, (3) minimum duration of toxicity, (4) reversibility of toxicity within a certain period of time, and (5) necessity to delay treatment or to reduce dose-intensity.