Occurrence Of Dose-limiting Toxicities Research Articles

P-123 A phase Ia/Ib, open-label, dose-escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy in patients with advanced gastrointestinal cancers

Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 is therefore an attractive therapeutic strategy in oncology, but some early TRAILR2 agonists showed limited clinical success due to low efficacy or severe hepatotoxicity. The tetravalent bispecific antibody BI 905711 represents a novel, liver-sparing, TRAILR2 agonist, which cross-links TRAILR2 with cadherin 17 (CDH17) to induce CDH17-dependent TRAILR2 oligomerisation. CDH17, a membrane protein highly expressed in gastrointestinal (GI) cancers, is not expressed in normal hepatocytes. Thus, using CDH17 as a liver-sparing anchor may avoid hepatotoxicity while increasing selectivity to cancer cells. In preclinical models of GI cancer, including colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), BI 905711 showed activity both as a single agent and in combination with chemotherapeutic agents (Garcia-Martinez et al., Mol Cancer Ther 2021;20:96–108). Preclinical studies also showed synergism of BI 905711 and SoC chemotherapy, particularly irinotecan. This phase Ia/Ib open-label, multicentre study (NCT05087992) aims to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE), pharmacokinetics (PK), and preliminary efficacy of BI 905711 in combination with chemotherapy (FOLFIRI; irinotecan, leucovorin, and fluorouracil) with or without bevacizumab in patients with advanced, refractory GI cancers. Up to 100 patients with histologically or cytologically confirmed, advanced, unresectable or metastatic GI cancers will be enrolled. In phase Ia, approximately 20 patients with CRC will receive intravenous BI 905711 at escalating doses (starting dose 0.6 mg/kg) on day 3 of 14-day cycles, plus FOLFIRI and bevacizumab (5 mg/kg IV infusion over 30 mins) on day 1. BI 905711 dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first two 14-day cycles). BI 905711 will be administered until disease progression, unacceptable toxicities or another reason requiring treatment discontinuation. In phase Ib, patients with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, patients who have progressed after prior oxaliplatin-based therapy will be randomised in a 2:1 ratio to receive FOLFIRI and bevazicumab with or without BI 905711. In the PDAC cohort, patients with CDH17-positive PDAC who have progressed after prior platin/gemcitabine-based first-line therapy will receive FOLFIRI plus BI 905711. In both cohorts, BI 905711 will be administered at the RDE determined in phase Ia. A safety run-in will be included in the PDAC cohort to confirm the RDE defined in phase Ia prior to enrolling further patients. Primary endpoints are the MTD based on the occurrence of DLTs (phase Ia), and confirmed objective response (OR) according to RECIST 1.1 (phase Ib). Secondary endpoints include PK assessments (phase Ia), progression-free survival, tumour shrinkage, duration of OR and disease control (phase Ib). Further endpoints include assessment of immunogenic response and pharmacodynamic biomarker modulation (including caspase activation and changes in circulating tumour DNA levels). Patient recruitment is active and the study is ongoing. NCT05087992. Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals Inc., was provided by Jane Saunders of Ashfield MedComms, an Ashfield Health Company, during the preparation of this abstract. The authors received no direct payment. Boehringer Ingelheim.

Initial findings from a first-in-human, multicenter, open-label study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.

2529 Background: ATOR-1017 is a human agonist Fcγ-receptor cross-linking dependent IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. Methods: In this first-in-human, dose escalation, multicenter, phase 1 study (NCT04144842), adult patients with solid tumors refractory to standard therapy were enrolled in single patient cohorts for doses up to 40 mg, and thereafter in cohorts of 3-6 patients, to receive ATOR-1017 in a 21-day cycle. Intra-patient dose escalation of ATOR-1017 is allowed depending on the occurrence of Dose-Limiting Toxicities (DLTs) during cycle 1. ATOR-1017 is administered intravenously as monotherapy every three weeks until unacceptable toxicity, progressive disease, or withdrawal of consent. The primary objectives of the study are to determine the maximum tolerated dose, assess adverse events (AEs), evaluate DLTs, and to determine the recommended phase 2 dose. Secondary objectives include pharmacokinetics (PK), immunogenicity, and clinical efficacy, assessed with CT scans using Immune Response Evaluation Criteria in Solid Tumors (iRECIST). Exploratory objectives include assessment of pharmacodynamic (PD) biomarkers. Results: 22 patients (18 females), median age 55 years (34-76) with solid tumors, previously treated with median of 4 (0-6) lines of chemotherapy and/or 2 (0-3) lines of immunotherapy, were included and received at least one cycle ATOR-1017. Nine dose levels have been evaluated; 0.38 mg, 1.5 mg, 5 mg, 15 mg; 40 mg, 100 mg, 200 mg, 360 mg, and 600 mg and dose escalation is ongoing. Treatment-related (TRAEs) were reported in 12 out of 22 patients (54.5%); most common (≥10%) were fatigue (13.6%) and neutropenia (13.6%). Five patients experienced a grade 3-4 TRAE; neutropenia (n = 2), febrile neutropenia (n = 1), chest pain (n = 1), increased liver enzymes (n = 1) and leukopenia/thrombocytopenia (n = 1). No patients discontinued due to TRAEs, no DLTs were observed, and the maximum tolerated dose has not been reached. The median time for patients in the study was 12 weeks (range 4-67). As per data cut-off, January 18, 2022, four patients remained on treatment and 18 patients had discontinued treatment. The reasons for discontinuation include confirmed disease progression (n = 10), clinical deterioration (n = 4), withdrawal of consent (n = 1), death due to disease progression (n = 3). Preliminary PK data showed dose-proportional kinetics. Dose-dependent increase in PD biomarkers demonstrated target-mediated biological activity and proof-of-mechanism. The best response was stable disease observed in a total of 10 patients (45%). Conclusions: ATOR-1017 is safe and well-tolerated at doses up to 600 mg and has shown biologic activity. No DLTs have been reported so far and dose escalation continues. Clinical trial information: NCT04144842.

Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: An open-label phase 1/2 study.

7545 Background: PD-1 inhibitors are a standard of care for R/R cHL but optimal therapy after anti–PD-1 therapy failure is yet to be defined. LAG-3/PD-1 coblockade has demonstrated antitumor activity in preclinical models. This multicohort phase 1/2 study (NCT03598608) evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 2 focused on pts with R/R cHL refractory to anti–PD-1 therapy. Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 2 had R/R cHL, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, pts from all cohorts received pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using an mTPI design. In part 2, pts received pembro + favezelimab at the established RP2D for up to 35 cycles. Primary end point was safety. Secondary end point was ORR. DOR, PFS, and OS were exploratory. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed among the first 6 pts from all cohorts in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in 15 additional pts at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. In cohort 2, 33 pts were enrolled; median age was 37 yrs, 64% had ECOG PS 0, and 94% had ≥4 prior lines of therapy. After a median follow-up of 16.5 mo, ORR for pts receiving favezelimab 800 mg (n = 29) was 31% (95% CI, 15-51; CR, 2 [7%]; PR, 7 [24%]); 66% of responders had an anti–PD-1–based regimen as most recent line of therapy at study entry. 23 of 29 pts (79%) had reduction from baseline in target lesions. Median DOR for pts who received favezelimab 800 mg was not reached (NR; 95% CI, 0+ to 14+ mo). For all pts in cohort 2, median PFS was 9 mo (95% CI, 5-15); 12-mo PFS rate was 39%. Median OS was 26 mo (95% CI, 26-NR); 12-mo OS rate was 91%. At database cutoff (Nov 1, 2021), 20 pts discontinued treatment (7 AEs, 11 PD/clinical progression, 2, withdrawal/physician decision). TRAEs occurred in 28 pts (85%); most common ( > 10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each); grade 3 or 4 TRAEs occurred in 6 pts (18%); 18% discontinued treatment due to TRAEs. No treatment-related deaths occurred. Conclusions: Favezelimab 800 mg + pembro 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated pts with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these pts. Clinical trial information: NCT03598608.

92MO Neoadjuvant nivolumab (NIVO) + palbociclib (PALBO) + anastrozole (ANA) for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) primary breast cancer (BC): CheckMate 7A8

Cyclin-dependent kinase (CDK) 4/6 inhibition + ER signaling blockade is a highly effective treatment option for metastatic ER+/HER2− BC. Preclinical studies show evidence of CDK 4/6 and programmed death-1 (PD-1) blockade synergy. CheckMate 7A8, a non-comparative, phase 2 study, evaluated neoadjuvant NIVO + PALBO + ANA in patients (pts) with ER+/HER2− primary BC. Here, we report safety outcomes from the safety run-in phase. Eligible pts were men or postmenopausal women with newly diagnosed, histologically confirmed, untreated ER+/HER2− BC with primary tumor ≥ 2 cm, an ECOG performance status of 0/1, and eligible for post-treatment surgery. Pts received NIVO 480 mg IV every 4 wks (1 cycle), PALBO 125 mg (dose level [DL] 1) or 100 mg (DL 2) PO once daily (QD) for 3 wks per cycle, and ANA 1 mg PO QD, for 5 cycles total/until disease progression. Primary endpoint (safety run-in phase) was the number of pts with occurrence of dose-limiting toxicity (treatment-emergent adverse events [AEs] within 4 wks of treatment start). As of safety data review on 6 May 2021, 21 pts (DL 1: n = 9; DL 2: n = 12) were treated. Most common grade ≥3 treatment-related AEs (TRAEs) were elevated alanine or aspartate aminotransferase, neutropenia, and decreased white blood cell count in DL 1 (n = 2 each; 22.2%), and decreased neutrophil count (n = 5; 41.7%) in DL 2. 5 pts (DL 1) and 4 pts (DL 2) discontinued treatment due to toxicity, mainly grade ≥3 hepatic TRAEs (Table). The study was closed on 27 July 2021 after safety run-in ended. Additional safety and preliminary efficacy data (database lock: 3 February 2022) will be presented.Table: 92MOTRAEs leading to discontinuation, n (%)Dose level 1 (n = 9)Dose level 2 (n = 12)Any gradeGrade 3/4Any gradeGrade 3/4Increased ALT2 (22.2)2 (22.2)1 (8.3)1 (8.3)Hypertransaminasaemia001 (8.3)1 (8.3)Increased AST2 (22.2)2 (22.2)00Increased transaminases1 (11.1)1 (11.1)01 (8.3)Febrile neutropenia1 (11.1)1 (11.1)00Rash1 (11.1)1 (11.1)00Pneumonitis1 (11.1)01 (8.3)0 Open table in a new tab Neoadjuvant NIVO + PALBO + ANA showed a higher incidence of grade ≥3 hepatic TRAEs than historical single-agent safety profiles. These findings show a potential safety risk for the use of endocrine therapy with PD-1 + CDK 4/6 blockade.

A Phase I, Single Ascending Dose Study ofGEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy.

PurposeTo establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA).DesignPhase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866).ParticipantsTwelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye.MethodsParticipants were assigned to the increasing dose cohorts and received 1 50-μl intravitreal injection of GEM103 at doses of 50 μg/eye, 100 μg/eye, 250 μg/eye, or 500 μg/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities.Main Outcome MeasuresSafety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a.ResultsNo dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 μg or more. Complement activation biomarkers were reduced 7 days after dose administration.ConclusionsA single intravitreal administration of GEM103 (up to 500 μg/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD.

KEYNOTE-B79 phase 1b trial to evaluate the allogeneic CAR T-cells CYAD-101 and pembrolizumab in refractory metastatic colorectal cancer patients.

TPS227 Background: The allogeneic chimeric antigen receptor (CAR) T-cell treatment CYAD-101 utilizes the NKG2D receptor that targets eight ligands expressed on tumor cells and also on stromal and immunosuppressive immune cells of the tumor microenvironment. CYAD-101 co-expresses a T-cell receptor (TCR) inhibitory peptide with the aim to eliminate the potential of graft versus host disease (GvHD), the main safety risk associated with engineered cells of allogeneic origin. In the previous alloSHRINK trial (NCT03692429), CYAD-101 was administered post FOLFOX preconditioning chemotherapy to 15 patients with progressive metastatic colorectal cancer (mCRC) who were previously treated with FOLFOX. Overall, the treatment was well tolerated with no evidence of GvHD. The disease control rate was 73.3% with two patients presenting a confirmed partial response per RECIST’s criteria (4 months and 8 months of duration from first CYAD-101 infusion) and nine had stable disease with a median duration of 4.6 months. Evidence of increase in the TCR repertoire and modulation of the cytokine profile post-treatment with CYAD-101 were observed implying that CYAD-101 may also be modulating the immune suppressive environment in patients mirroring what was demonstrated in pre-clinical models. We considered that a sequential therapy with the anti-PD1 monoclonal antibody pembrolizumab to further release the anti-tumor potential of this expanded T-cell population may drive deeper, more durable and new clinical responses beyond that currently demonstrated with the CAR T-cells alone. Methods: The phase 1b KEYNOTE-B79 trial (NCT04991948) will evaluate, according to a Simon’s two stage study design, the safety and clinical activity of three consecutive infusions of CYAD-101 (1x109 cells per infusion) post FOLFOX preconditioning chemotherapy with two-week interval between cycles, followed by pembrolizumab treatment (200 mg administered every three weeks for up to two years) in microsatellite stable/mismatch-repair proficient mCRC patients with recurrent/progressing disease after at least one metastatic line of therapy, which must include FOLFOX chemotherapy. The pembrolizumab treatment will be initiated 3 weeks after the last CYAD-101 infusion to fall outside the classical time window of potential CAR T-cell toxicities (e.g., cytokine release syndrome). The co-primary endpoints of the trial are the occurrence of dose-limiting toxicities (DLTs) at any time from the first FOLFOX preconditioning treatment up to 3 weeks after the first pembrolizumab treatment and the objective response rate (ORR) at the tumor assessment planned 6 weeks after the first pembrolizumab treatment administration. The KEYNOTE-B79 study will be initiated in Q4-2021 in five sites in USA and Europe. Clinical trial information: NCT04991948.

An Australasian Leukemia Lymphoma Group (ALLG) Phase 2 Study to Investigate Novel Triplets to Extend Remission with Venetoclax in Elderly (INTERVENE) Acute Myeloid Leukemia

An Australasian Leukemia Lymphoma Group (ALLG) Phase 2 Study to Investigate Novel Triplets to Extend Remission with Venetoclax in Elderly (INTERVENE) Acute Myeloid Leukemia

A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma

Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol

IntroductionThe undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously...

Abstract CT104: Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety results of the INTR@PID LUNG 024 study

Abstract Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. The global, phase 1b/2 INTR@PID LUNG 024 (NCT03840915) study evaluates bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC. Here we report cumulative safety, which represents the first report of safety results from a clinical study with a bintrafusp alfa 2400-mg every-three-weeks (Q3W) regimen. Methods: Adults with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 are included. In cohorts A, B, and C, patients must not have received prior systemic therapy; in cohort D, patients must have had progression on previous anti-PD-(L)1 therapy. Patients received bintrafusp alfa 2400 mg Q3W intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or combination with pemetrexed in cohort A) for up to 31 cycles. The occurrence of dose-limiting toxicities (DLTs) was assessed during a 3-week observation period. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Additionally, in cohort A, patients from the safety and expansion parts will be assessed for preliminary efficacy. Results: As of October 7, 2020, 64 patients received bintrafusp alfa in combination with CT. Of the 35 patients included in the DLT analysis, 4 experienced 1 DLT according to the safety monitoring committee (A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). The cumulative safety is reported (Table). Conclusions: The combination of bintrafusp alfa 2400 Q3W in combination with CT was well tolerated. No new safety signals were identified. Cohort A (n=34)Cohort B (n=9)Cohort C (n=9)Cohort D (n=12)Treatment-emergent adverse events, n (%)Any*34 (100.0)9 (100.0)9 (100.0)12 (100.0)Grade ≥324 (70.6)6 (66.7)7 (77.8)12 (100.0)Grade ≥412 (35.3)3 (33.3)5 (55.6)6 (50.0)Serious22 (64.7)3 (33.3)6 (66.7)9 (75.0)Leading to death3 (8.8)1 (11.1)00Leading to dose reduction of CT9 (26.5)2 (22.2)5 (55.6)4 (33.3)Leading to permanent discontinuation of bintrafusp alfa12 (35.3)04 (44.4)4 (33.3)Leading to permanent discontinuation of CT13 (38.2)1 (11.1)4 (44.4)3 (25.0)Treatment-related adverse events, n (%)Any bintrafusp alfa-related adverse events28 (82.4)9 (100.0)9 (100.0)12 (100.0)Bintrafusp alfa-related serious adverse events9 (26.5)01 (11.1)3 (25.0)Bintrafusp alfa-related adverse events leading to death0000Any chemotherapy-related adverse events31 (91.2)8 (88.9)9 (100.0)12 (100.0)Chemotherapy-related serious adverse events10 (29.4)1 (11.1)4 (44.4)7 (58.3)Chemotherapy-related adverse events leading to death0000Adverse events of special interest, n (%)Skin lesions†2 (5.9)04 (44.4)1 (8.3)Immune-related adverse event15 (44.1)3 (33.3)5 (55.6)6 (50.0)Infusion-related reaction3 (8.8)1 (11.1)1 (11.1)1 (8.3)Anemia16 (47.1)5 (55.6)9 (100.0)9 (75.0)*Most common (≥50%) treatment-emergent adverse events in any cohort included anemia (cohort B: 55.6%; cohort C: 100.0%; cohort D: 75.0%), nausea (cohort A: 52.9%, cohort C: 66.7%), pruritus (cohort C: 66.7%), asthenia (cohort C: 55.6%; cohort D: 58.3%), neutropenia (cohort C: 55.6%), decreased appetite (cohort D: 50.0%), and diarrhea (cohort D: 50.0%).†Defined as actinic keratosis, basal cell carcinoma, Bowen's disease, hyperkeratosis, keratoacanthoma, lip squamous cell carcinoma, and squamous cell carcinoma of skin. Actinic keratosis, hyperkeratosis, and keratoacanthoma were reported in this study. Citation Format: Christian Rolfo, Laurent Greillier, Remi Veillon, Firas Badin, Francois Ghiringhelli, Nicolas Isambert, Astrid Paulus, Marc Lambrechts, Italia Grenga, Xiaoli You, Andre Koenig, Sandrine Hiret. Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety results of the INTR@PID LUNG 024 study [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 CT104.

Modulated electro-hyperthermia with weekly paclitaxel or cisplatin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: The KGOG 3030 trial.

The present study (KGOG 3030) aimed to evaluate the safety of modulated electro-hyperthermia (mEHT) therapy with weekly administration of paclitaxel or cisplatin in female patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. A total of 12 patients were randomized into the paclitaxel or cisplatin arm at a 1:1 ratio. Patients received weekly administration of paclitaxel (70 mg/m2) or cisplatin (40 mg/m2) intravenously on days 1, 8 and 15, and underwent mEHT therapy for 1 h on days 1, 4, 8, 11, 15, 18, 21 and 24 for each 4-week cycle. The primary endpoint was the occurrence of dose-limiting toxicity (DLT). The secondary endpoints were treatment-emergent adverse events (TEAEs), objective response rate, carbohydrate antigen 125 (CA125) response rate, progression-free survival (PFS) and overall survival (OS). In total, 16 patients were recruited, but four patients dropped out. None of the 12 remaining patients (6 each in the two arms) experienced DLT. Overall, 0 and 4 grade 3 TEAEs (anemia, nausea, neutrophil count decreased and platelet count decreased) occurred in the paclitaxel and cisplatin arm, respectively. Furthermore, one confirmed partial response and two CA125 responses were observed in the cisplatin arm. The median PFS time in the paclitaxel and cisplatin arms was 3.0 months (range, 1.7-4.6 months) and 6.8 months (range, 3.9-11.8 months), respectively, while the median OS time was 11.5 months (range, 8.4-28.8+ months) and not reached (range, 3.9-38.5+ months), respectively. In conclusion, mEHT therapy with weekly paclitaxel or cisplatin appeared safe and warrants further investigation. The present trial was registered with www.clinicaltrials.gov on January 22, 2015 (trial registration no. NCT02344095).

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

VOTRAGE study: Phase I dose-escalation study of pazopanib in unfit older patients

BackgroundPazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment. Patients and methodsVOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD). PK data were compared with those obtained in younger adult patients in a population PK analysis. ResultsEighteen patients with a median age of 82.5 years (range 75–91) were included in three dosing cohorts (400, 600, and 800 mg daily). Three dose-limiting toxicities (DLT) were observed in five patients at 800 mg and one DLT at 600 mg in six evaluable patients. MTD was defined as level 2 dose (600 mg). Individual oral clearance was not correlated with age. A relationship was observed between the occurrence of DLT and pazopanib plasma exposure. Decreased oral bioavailability of pazopanib when given with proton-pump inhibitors was confirmed in this group of patients. ConclusionWe recommend performing geriatric assessment in patients older than 75 and starting pazopanib at 600 mg per day in unfit older patients. Therapeutic drug monitoring appears very helpful in this population.

A Pilot/Safety Study of sEphB4-Hsa in Combination with a Hypomethylating Agent for Patients with Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia Previously Treated with a Hypomethylating Agent

Background: Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm that results in bone marrow failure and frequently leads to acute myeloid leukemia (AML). Hypomethylating agents (HMA) are the only FDA-approved treatment for MDS and among few options for chemotherapy-ineligible patients with AML. There are limited options for patients in whom HMA therapy fails and who are not candidates for allogeneic stem cell transplant, so therapies that complement or restore sensitivity to HMAs are needed. Studies have shown increases in bone marrow microvessel density (MVD) and angiogenic markers in patients with MDS and AML. A decrease in MVD has been shown to correlate with response to hypomethylating agents in MDS. A receptor-ligand interaction, comprised of receptor EphB4 and membrane localized ligand EphrinB2, mediates angiogenesis in normal tissue and appears to be a target unique to many cancer types. We have previously shown EphB4 to be highly expressed and a driver of leukemic cell survival in a subset of AML patients. Our group has developed a human fusion protein, sEphB4-HSA, that blocks bidirectional signaling induced by EphB4-EphrinB2 interaction to inhibit tumor cell proliferation and angiogenesis. In phase I clinical trials of sEphB4-HSA in various tumor types, there were no myelosuppressive effects and minimal toxicity. Given its safety in phase I and potential to inhibit leukemic cell proliferation and angiogenesis, we proposed a pilot trial to evaluate the safety of sEphB4-HSA in combination with HMAs in MDS and AML patients who have failed treatment with HMAs. Methods: This pilot study was designed to enroll 6 patients with relapsed/refractory intermediate or high-risk MDS and 6 patients with AML refractory to or relapsed to HMA treatment and who are deemed unfit for chemotherapy. Treatment consisted of sEphB4-HSA 15 mg/kg IV every 2 weeks in combination with the FDA-approved HMA most recently or currently being used for treatment (decitabine 20mg/m2 IV/1hr on days 1 to 5 every 28 days or azacitidine 75mg/m2 SC or IV on days 1 to 7 every 28 days). Patients were treated for as long as they were receiving clinical benefit up to 12 months. The primary endpoint was toxicity and tolerability of sEphB4-HSA in combination with HMA. Toxicity was assessed and graded after each cycle according to the CTCAE version 4. Tolerability was defined as the ability to complete two cycles of treatment without the occurrence of dose-limiting toxicity. A secondary efficacy endpoint was to assess best overall response, based on the IWG Working Group Criteria for MDS and AML, during the first two cycles of treatment. Enrollment was stopped after 7 patients due to expiration of funding. Results: Three patients with intermediate-risk MDS were treated for a median duration of 6 cycles (2-12) and 4 patients with AML were treated for 2 cycles. Median age was 75.5 years (67.9-84.8) and 57.1% were male. HMA included azacitadine in 6 patients and decitabine in one patient. There were no dose-limiting toxicities. There were 8 grade 3/4 events attributed to HMA, which included: neutropenia (2), thrombocytopenia (3), and leukopenia (3). There were 3 grade 3/4 events attributed to sEphB4, which included: febrile neutropenia (1), leukopenia (1), and hypertension (1). Of the MDS patients, 2 had stable disease, 1 patient after 2 cycles and 1 patient after 4 cycles. One patient achieved a hematologic improvement-erythroid after 6 cycles. AML patients had no disease response. Reasons for treatment discontinuation were death (1), disease progression (2), patient's decision (1), physician's decision (2), and hospice (1). Notably, a comparison of bone marrow biopsies at baseline and after 8 weeks of treatment demonstrated a decrease in MVD (Figure 1). Discussion: This pilot study found sEphB4 in combination with HMAs to be tolerable with no significant toxicity beyond that expected with HMA therapy and associated with potential clinical benefit in MDS patients. Improvement in abnormal bone marrow MVD may indicate a potential for sEphB4-HSA plus HMA therapy to alter the malignant microenvironment in MDS/AML. Disclosures No relevant conflicts of interest to declare.

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

A phase II trial of nivolumab (NIVO) + palbociclib (PAL) + anastrozole (ANA) in postmenopausal women and men with estrogen receptor (ER)+/human epidermal growth factor 2 (HER2)- primary breast cancer (BC): CheckMate 7A8.

TPS1105 Background: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with ER signaling blockade is an efficient treatment approach for patients (pts) with metastatic hormone receptor-positive, HER2− BC. Preclinical data suggest synergistic activity of CDK 4/6 inhibition and PD-1 blockade; in a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with phased administration of ABE + PD-L1 therapy. Methods: CheckMate 7A8 (NCT04075604) is a randomized, noncomparative, multicenter, phase 2 study evaluating PAL + ANA +/- NIVO in postmenopausal pts with ER+, HER2− primary BC. After determining safe doses for NIVO combination regimens in the safety run-in phase, pts will be randomized in a 4:4:3 ratio to 1 of 3 treatment arms (Table) stratified by PD-L1 expression, node status and tumor size. Following treatment, all pts will undergo surgery and safety follow-up. Eligible pts are postmenopausal women and men with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; suitable for neoadjuvant endocrine monotherapy and surgery; ECOG PS of 0–1; have baseline tumor tissue available; willing to undergo on-treatment research biopsy and tissue collection at surgery. Primary endpoints are number of pts with occurrence of dose-limiting toxicity (safety run-in phase) and residual cancer burden 0–I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, objective response rate and breast-conserving surgery rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes and potentially predicting treatment sensitivity. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04075604 . [Table: see text]

Abstract P5-11-15: Estetrol for treatment of advanced ER+/HER2- breast cancer

Abstract Introduction: A high dose of the fetal estrogen estetrol (E4) is anticipated to have anti-tumor effects in patients with advanced, anti-estrogen resistant, ER+/HER2- breast cancer (BC). It will most likely also improve patient’s quality of life by reducing symptoms of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, vaginal dryness, mood changes and depression, bone loss and fractures and cognition. The ABCE4 study is performed in Germany in this patient population. The main objectives of the study are to assess safety and tolerability of three doses of E4, to determine anti-tumor response and to evaluate estrogen deficiency symptoms. Study design: This is a multi-center, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of 3 patients receive 20 mg, 40 mg and 60 mg E4 per day by oral administration. Dose limiting toxicity (DLT), safety and wellbeing are evaluated after 4, 8 and 12 weeks of treatment. Occurrence of DLT at completion of phase IB after 4 weeks treatment determines escalation to the next higher dose. Objective anti-tumor effects are assessed by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Thereafter treatment may continue based on an evaluation of the patient and her treating physician. In view of the small numbers required for this study design no statistical testing was performed. Results: A total of 12 postmenopausal women with progressive, heavily pre-treated advanced BC have been enrolled. Nine patients completed Phase IB. One patient in the 20 mg group discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. She died 3 weeks later. Eight patients completed both the Phase IB and IIA part of the study. None of the patients experienced a DLT. All three E4 doses were well tolerated by all patients. In total 38 adverse events were reported. Adverse events were mainly of mild or moderate intensity. The following 8 events were considered possibly related to E4 treatment: increased endometrial thickness, spotting (2 patients), dry skin, pruritus, edema, fatigue (2 patients), alopecia and acid regurgitation. Seven events fulfilled the criteria of seriousness from which one was considered to be related to E4 treatment. This patient experienced moderate vaginal bleeding after 36 weeks treatment with 20 mg E4 and was hospitalized for hysteroscopy and endometrial ablation with full recovery thereafter. Importantly five of the eight patients who completed treatment with E4 reported subjective improvement and “felt much better” than before the start of E4 treatment. This was described by one of the patients as: ‘”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. Five patients completing 12 weeks E4 treatment showed objective anti-tumor effects with stable disease (n=4) and one remission. All five continued E4 treatment. Tumor assessment after 24 weeks of E4 treatment showed again stable disease in 4 patients. Conclusion: We conclude that daily doses of 20 mg, 40 mg and 60 mg E4 are well tolerated without DLTs. The majority of patients experienced favorable subjective effects and four patients treated for 24 weeks or longer showed stable disease and tumor remission respectively. Treatment with E4 meets the criteria for further investigation and development of E4 as a new drug for the treatment of anti-estrogen resistant advanced breast cancer. Final dose selection of E4 will take place in September 2019. Citation Format: Marcus Schmidt, Arnd Hönig, Yvette Zimmerman, Carole Verhoeven, Katrin Almstedt, Marco Battista, Hans Georg Lenhard, Jan Krijgh, Herjan Coelingh Bennink. Estetrol for treatment of advanced ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-15.

Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer

Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC. Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (> 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up. Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded. Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method. No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com. Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-02.

Phase II Study of Midostaurin + Chemotherapy in Pediatric Patients with Untreated, Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML)

Background: In pediatric patients with AML, the presence of FLT3-internal tandem duplication (ITD) mutation is indicative of high-risk disease and confers a worse prognosis and a greater chance of relapse. Midostaurin is a multikinase inhibitor with potent activity against both mutated and non-mutated FLT3. In adult patients with FLT3-mutated AML, midostaurin in combination with chemotherapy has demonstrated good safety/tolerability and significantly improved overall survival (OS) and event-free survival (EFS) compared with placebo + chemotherapy. We present here the design of an ongoing phase II study (NCT03591510) evaluating midostaurin combined with standard chemotherapy and as a single-agent post-consolidation therapy in newly diagnosed pediatric patients with FLT3-mutated AML, other than acute promyelocytic leukemia. Study Design and Methods: This open-label, single-arm study is composed of 2 parts. For Part 1, the primary objective is to determine the recommended phase II dose (RP2D) of midostaurin in combination with chemotherapy, as determined by the occurrence of dose-limiting toxicities. For Part 2, in which patients will receive the RP2D of midostaurin, the primary objective is to evaluate the efficacy of midostaurin + chemotherapy as measured by the EFS rate at 24 mo (for regulatory purposes outside the US) or to assess the safety/tolerability of midostaurin + chemotherapy (for regulatory purposes within the US). Secondary objectives include safety/tolerability (outside US) and EFS at 24 mo (within US), other efficacy parameters (including OS, complete remission [CR], CR with incomplete blood count recovery [CRi], cumulative incidence of relapse, and minimal residual disease-negative status), and characterization of the pharmacokinetics of midostaurin. Eligible patients are aged 3 mo to < 18 yr with expected survival of > 12 wk, have a Lansky or Karnofsky performance status of ≥ 60, and have previously untreated de novo AML with FLT3 mutation: ITD and/or mutation in the tyrosine kinase domain, with mutant/wild-type signal ratio cutoff of ≥ 0.05. Exclusion criteria include any concurrent malignancy, Philadelphia chromosome or BCR-ABL1-positive AML, AML associated with Down syndrome, secondary AML, symptomatic leukemic central nervous system involvement, bone marrow failure syndrome, or prior treatment with a FLT3 inhibitor. Patients are to receive 5 treatment blocks: 2 of standard induction (Blocks 1-2) and 3 of consolidation (Blocks 3-5) chemotherapy, each with sequential twice-daily (BID) oral midostaurin. In Part 1 of the study, midostaurin will be given at a starting dose of 30 mg/m2 BID; dose escalation and determination of RP2D will be facilitated by a Bayesian hierarchical logistic regression model guided by escalation with overdose control principle. In Part 2, midostaurin will be administered at the RP2D. Induction therapy will be the local standard chemotherapy regimen with midostaurin starting after 24 hr from identification of FLT3 abnormalities and continuing for 14 d for Block 1, and FLADx (fludarabine + high-dose cytarabine on D1-5, daunorubicin on D2, 4, 6) with sequential midostaurin on D8-21 for Block 2. Patients demonstrating CR or modified CRi will proceed to consolidation with the following chemotherapy regimens, each with sequential midostaurin on D8-21: HAM (high-dose cytarabine on D1-3, mitoxantrone on D3, 4) for Block 3, HA3E (high-dose cytarabine on D1-3, etoposide on D1-5) for Block 4, and HiDAC (high-dose cytarabine on D1-3) for Block 5. Patients must be in continued remission (CR or modified CRi) to receive each block of consolidation therapy. Patients who complete Block 5 and remain in remission will proceed to 12 × 28-d cycles of post-consolidation therapy with single-agent midostaurin. Patients may undergo allogeneic hematopoietic stem cell transplantation at any time at the investigator's discretion. Overall, the aim is to recruit a minimum of 52 patients, including at least 49 at the RP2D dose. This study is currently enrolling patients at 13 centers in 7 countries (as of July 26, 2019), and a total of 37 centers in 14 countries are planned. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; Jazz: Other: Participation in Advisory Boards, Research Funding; CSL Behring: Research Funding; Roche: Research Funding. Zwaan:BMS: Research Funding; Servier: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Roche: Consultancy; Incyte: Consultancy. Hoenekopp:Novartis Pharma AG Basel: Employment, Equity Ownership. Niolat:Novartis Pharma: Employment. Ifrah:Novartis: Employment. Noel-Baron:Novartis: Employment, Equity Ownership. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Midostaurin is a kinase inhibitor approved in combination with chemotherapy for the treatment of FLT3-mutated AML in adults; the study reported here is in pediatric patients with FLT3-mutated AML.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors (NepoMUC): a phase I dose escalation trial

BackgroundMore than 25% of patients with solid cancers develop intracerebral metastases. Aside of surgery, radiation therapy (RT) is a mainstay in the treatment of intracerebral metastases. Postoperative fractionated stereotactic RT (FSRT) to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recurrence. However, FSRT has to be delayed until a sufficient wound healing is attained; hence systemic therapy might be postponed. Neoadjuvant stereotactic radiosurgery (SRS) might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy. Here, we conducted a study to find the maximum tolerated dose (MTD) of neoadjuvant SRS for intracerebral metastases.MethodsThis is a single-center, phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital, Technical University of Munich. The rule-based traditional 3 + 3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied. The primary endpoint is the MTD for which no dose-limiting toxicities (DLT) occur. The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 continuously during the study until the first follow-up visit (4–6 weeks after surgery). Secondary endpoints include local control rate, survival, immunological tumor characteristics, quality of life (QoL), CTCAE grade of late clinical, neurological, and neurocognitive toxicities. In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS. Depending on the occurrence of DLT up to 72 patients will be enrolled. The recruitment phase will last for 24 months.DiscussionNeoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity, such as better target volume definition with subsequent higher efficiency of eliminating tumor cells, and lower damage to surrounding healthy tissue, and much-needed systemic chemotherapy could be initiated more rapidly.Trial registration The local ethical review committee of Technical University of Munich (199/18S) approved this study on September 05, 2018. This trial was registered on German Clinical Trials Register (DRKS00016613; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016613) on January 29, 2019.