Sacituzumab govitecan (SG) in patients (pts) with previously treated metastatic endometrial cancer (mEC): results from a phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6081-6081
Author(s):  
Alessandro Santin ◽  
Takefumi Komiya ◽  
David M. Goldenberg ◽  
Robert M. Sharkey ◽  
Quan Hong ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Bystander Effect ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Objective Response ◽  
Surface Glycoprotein ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Cell Surface Glycoprotein

6081 Background: Unselected pts with EC who progressed on prior chemotherapy have a poor prognosis with limited treatment options. SG is a novel antibody-drug conjugate that targets Trop-2, a cell surface glycoprotein highly expressed in many epithelial tumors. It is conjugated to deliver SN-38, the active metabolite of irinotecan, via a proprietary hydrolyzable linker. Preclinical studies show SG has activity against chemotherapy-resistant EC and significant bystander effect against EC with heterogenous Trop-2 expression (Perrone E. Mol Oncol. 2019). Methods: The phase I/II basket study (NCT01631552) evaluated pts unselected for Trop-2 with advanced solid tumors who received intravenous SG (days 1 and 8 of 21-day cycles), until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment by RECIST 1.1. We report results for mEC pts who progressed after ≥1 prior systemic therapy and were treated with SG 10 mg/kg. Endpoints include safety, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 18 mEC pts (all women; 17 white and 1 black; median age 69 years [range, 41–76]) had a median 3.5 (range 2–6) prior lines of therapy. All pts received prior treatment with platinum therapies. At a median follow-up of 12.7 months, the ORR (95% CI) was 22.2% (6.4–47.6), with 4 partial responses. CBR (95% CI) was 44.4% (21.5–69.2), with 8 of 18 pts having either an objective response or stable disease ≥6 months. The DOR of responders ranged from 9.1 to 26.6 months, with 2 of 4 responders having a duration of ≥18 months. Median PFS (95% CI) was 3.2 months (1.9–9.4), and median OS (95% CI) was 11.9 months (4.7–not calculable). Key grade ≥3 TRAEs in the overall basket study safety population (n=495) included neutropenia (28%), neutrophil count decrease (14%), anemia (10%), diarrhea (8%), fatigue (6%), and febrile neutropenia (5%). A similar safety profile was seen in the mEC cohort. Conclusions: Median OS in unselected pts with mEC who progressed on prior platinum therapy is ~10 months with an ORR of ~10%. SG monotherapy showed clinical activity in pts with relapsed/refractory mEC, consistent with previous preclinical findings, and support further clinical investigation (NCT04251416). The phase II TROPiCS-03 (NCT03964727) study in pts with metastatic solid tumors selected based on elevated Trop-2 expression by a validated IHC assay will also provide further insights. Clinical trial information: NCT01631552.

Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 354-354 ◽  
Author(s):  
Scott T. Tagawa ◽  
Bishoy Morris Faltas ◽  
Elaine Tat Lam ◽  
Philip James Saylor ◽  
Aditya Bardia ◽  
...  
Keyword(s):  
Phase I ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Metastatic Urothelial Cancer

354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11036-11036
Author(s):  
John H. Strickler ◽  
Shannon McCall ◽  
Andrew B. Nixon ◽  
Herbert Pang ◽  
Christel Rushing ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Exact Test ◽  
Src Activation ◽  
Expansion Cohort

11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.

scholarly journals First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

2020 ◽  
Vol 38 (16) ◽  
pp. 1824-1835 ◽  
Author(s):  
Raffit Hassan ◽  
George R. Blumenschein ◽  
Kathleen N. Moore ◽  
Alessandro D. Santin ◽  
Hedy L. Kindler ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Phase Ii Studies ◽  
Antibody Drug

PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

408 Phase I, first-in-human trial evaluating BI 1387446 (stimulator of interferon genes [STING] agonist) alone and combined with BI 754091 (anti-programmed cell death [PD]-1) in solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A433-A433
Author(s):  
Kevin Harrington ◽  
Eileen Parkes ◽  
Jared Weiss ◽  
Mathew Ingham ◽  
Andrés Cervantes ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Objective Response ◽  
Clinical Activity ◽  
Type I ◽  
List Type ◽  
Intratumoral Administration ◽  
Tumor Lesion ◽  
Number Of Patients ◽  
Sting Pathway

BackgroundActivation of the STING pathway in intratumoral immune cells leads to increased type I interferon production, promoting recruitment and priming of T-cells against tumor antigens, and providing anti-tumor activity.1 Intratumoral administration of STING agonists has resulted in notable therapeutic activity in animal models.1 STING agonists have also shown clinical activity in patients, which was more pronounced when combined with an anti-PD-1 antibody.2,3 BI 1387446 potently and highly selectively activates the STING pathway; BI 754091 is a humanized IgG4 anti-PD-1 monoclonal antibody. Intratumoral administration of BI 1387446 resulted in tumor regression, and enhanced the activity of anti-PD-1 therapy in syngeneic tumor models.4MethodsNCT04147234 is a first-in-human, Phase I, open-label, multicenter trial of BI 1387446 in patients aged ≥18 years with advanced, unresectable and/or metastatic malignant solid tumors. Patients (up to ~122) will be enrolled from ~six sites across Europe and the USA. The main objectives are to characterize safety and determine the maximum tolerated dose (MTD) for BI 1387446 ± BI 754091. BI 1387446 will be administered intratumorally at increasing doses as monotherapy in Arm A, and in combination with BI 754091 (240 mg every three weeks, intravenously) in Arm B. In both arms, BI 1387446 will be administered in superficial lesions. In a potential third arm, Arm C, BI 1387446 will be administered in deep/visceral lesions in combination with intravenous BI 754091. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control.For trial eligibility, patients must have exhausted standard treatment options, have ≥1 tumor lesion suitable for injection, ≥1 additional tumor lesion amenable to biopsy, and ECOG performance status of 0/1. Treatment will continue until progressive disease, unacceptable toxicity, other withdrawal criteria, or a maximum treatment duration of 34 cycles (for cycle 19 and onwards, administration of BI 1387446 is applicable for patients with a partial response), whichever occurs first. Primary endpoints are the MTD based on number of dose-limiting toxicities (DLTs), and number of patients with DLTs in the MTD evaluation period. Secondary endpoints are objective response based on RECIST 1.1, and best percentage change from baseline in size of target and injected lesions. Paired pre- and post-treatment biopsies of injected- and non-injected lesions and peripheral blood will be collected to assess pharmacodynamic changes associated with treatment. The trial is currently open for recruitment.ResultsN/AConclusionsN/AAcknowledgementsMedical writing assistance, supported financially by Boehringer Ingelheim, was provided by Steven Kirkham, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this abstract.Trial RegistrationNCT04147234Ethics ApprovalNot applicable.ConsentNot applicable.ReferencesCorrales L, et al. J Clin Invest 2016;126:2404–2411.Meric-Bernstam F, et al. 33rd Ann Mtg and Pre-Conf Programs of the Society for Immunotherapy of Cancer (SITC), Washington, November 7–11 Nov 2018 (Poster #P309). 2018.Harrington K, et al. 43rd Ann Cong of the European Society for Medical Oncology (ESMO), Munich, 19–23 Oct 2018 (Poster #5475). 2018.Gremel G, et al. American Association for Cancer Research (AACR), Virtual Meeting, 22–24 Jun 2020 (Poster #4522). 2020.

First-in-human phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: Dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9072-9072 ◽  
Author(s):  
Anas Gazzah ◽  
Sophie Cousin ◽  
Valentina Boni ◽  
Charles Ricordel ◽  
Tae Min Kim ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Interim Analysis ◽  
Phase 1 ◽  
Surface Glycoprotein ◽  
Advanced Solid Tumors ◽  
Antibody Drug Conjugate ◽  
Cell Surface Glycoprotein ◽  
Grade 3 ◽  
Expansion Cohort

9072 Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types. This Phase 1, open-label, dose-escalation, dose-expansion study (NCT02187848) investigated SAR408701, a DM4 conjugated ADC targeting CEACAM5, in pts with advanced solid tumors. During dose escalation, maximum tolerated dose (MTD) of SAR408701 was 100 mg/m2 IV once every 2 weeks in 14-day cycles. Interim analysis of an ongoing expansion cohort in pts with NSQ NSCLC with CEACAM5 expression in ≥ 50% of the tumor cell population is reported. Methods: SAR408701 was administered at MTD. Primary endpoint: overall response rate (ORR; expansion phase). Secondary endpoints include safety and pharmacokinetics (PK). Tumor assessments were performed every 4 cycles (8 weeks). Results: As of Aug 2, 2018, 22 pts with NSQ NSCLC (21 adenocarcinoma; 1 not yet reported) received SAR408701 at MTD. Median age: 60 years; male: 72.7%; ECOG PS (n = 21): 0 = 38.1%, 1 = 61.9%. Median number of prior anticancer therapies for advanced disease was 3; 66.7% (14/21) received ≥ 3 lines; 59.1% had prior anti-tubulin-based treatments. Pts received a median of 6.5 cycles. 15 pts discontinued due to progressive disease and 1 due to an adverse event (AE; peripheral neuropathy); 6 pts remain on study. ORR was estimated at 22.7% (5/22 pts; 90% CI 11.5–39.9); 40.9% had stable disease. Most frequently occurring all-grade treatment-emergent AEs (TEAEs) were corneal events (40.9%; including keratitis 22.7% [1 Grade 3] and keratopathy 18.2%), dyspnea (31.8%; 5 Grade ≥ 3), asthenic conditions (31.8%) and diarrhea (27.3%). 6 pts had ≥ 1 dose modification due to a TEAE. PK analysis was performed in 14 pts at Cycle 1; mean Cmax, AUC, clearance and t1/2z were 53.1 µg/mL, 297 µg.day/mL, 0.685 L/day and 6.19 days, respectively. Conclusions: In pts with advanced NSQ NSCLC and CEACAM5 expression in ≥ 50% of tumor cells, SAR408701 had a favorable safety profile. Interim analysis of 22 pts achieved the predefined boundary for efficacy (≥ 4 of 30 pts). These data support further development in NSQ NSCLC. Funding: Sanofi Clinical trial information: NCT02187848.

Phase I expansion study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC): Preliminary efficacy, safety, and biomarker results in patients with previously treated metastatic ovarian cancer (OC) or non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3549-3549
Author(s):  
Debra L. Richardson ◽  
Minal A. Barve ◽  
James Fredric Strauss ◽  
Susanna Varkey Ulahannan ◽  
Kathleen N. Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Objective Response ◽  
Phosphate Transport ◽  
Clinical Activity ◽  
High Grade ◽  
Antibody Drug Conjugate ◽  
Tumor Biopsy ◽  
Peritoneal Cancer

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses >20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .

A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing, advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
Aaron Scott Mansfield ◽  
David S. Hong ◽  
Christine L. Hann ◽  
Anna F. Farago ◽  
Himisha Beltran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Tumor Lysis Syndrome ◽  
Safety Data ◽  
Malignant Neoplasm ◽  
Advanced Solid Tumors ◽  
Antibody Drug Conjugate

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

scholarly journals A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Aaron S. Mansfield ◽  
David S. Hong ◽  
Christine L. Hann ◽  
Anna F. Farago ◽  
Himisha Beltran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Medullary Thyroid Cancer ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Medullary Thyroid ◽  
Neuroendocrine Prostate Cancer ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Neuroendocrine Carcinomas

AbstractDelta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

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