scholarly journals Phase 1b/2 study to assess the safety, tolerability, and clinical activity of BGB-290 in combination with temozolomide in patients with locally advanced or metastatic solid tumors

2017 ◽  
Vol 28 ◽  
pp. v139-v140
Author(s):  
M. Johnson ◽  
B. Benson ◽  
R. Wei ◽  
R. Brachmann ◽  
M.D. Galsky
Keyword(s):  
Solid Tumors ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

Selinexor in combination with weekly paclitaxel in patients with advanced or metastatic solid tumors: Results of an open label, single-center, multiarm phase 1b study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5565-5565
Author(s):  
Shannon Neville Westin ◽  
Siqing Fu ◽  
Apostolia Maria Tsimberidou ◽  
Sarina Anne Anne Piha-Paul ◽  
Fechukwu Akhmedzhanov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Clinical Benefit ◽  
Nuclear Export ◽  
Nuclear Accumulation ◽  
Weekly Paclitaxel ◽  
Clinical Activity ◽  
Single Center ◽  
Open Label ◽  
Phase 1B

5565 Background: Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export (SINE) which blocks Exportin-1 (XPO1) leading to nuclear accumulation and activation of tumor suppressor proteins and prevention of translation of proto-oncogenes. Weekly paclitaxel is a standard chemotherapy regimen used in various tumor types. Preclinical models show that selinexor with paclitaxel exerts antitumor activity against multiple solid tumors. Our objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. Methods: This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor (twice weekly orally) and weekly paclitaxel (80mg IV 2 week on, 1 week off) was employed as one of 13 parallel arms. Two dose levels (DL) of selinexor were explored: DL1 selinexor 60mg; DL2 selinexor 80mg. Patients (pts) with advanced or metastatic solid tumors were eligible if they had adequate bone marrow and organ function. There was no limit on prior lines of therapy. Efficacy was evaluated using RECIST 1.1. Progression free survival (PFS) was defined as time from treatment until disease progression or death. Results: Of 35 pts treated, all were evaluable for toxicity, and 31 (88%) were evaluable for response. Pt diagnoses included ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Pts had a median of four prior therapies (range 1-10), and 47% had a prior taxane. All pts with ovarian cancer had platinum resistant/refractory disease; high grade serous histology was most common. There were no DLTs and DL1 was chosen as the RP2D given its long term tolerability. 97% of pts had at least one treatment-emergent adverse event (TEAE) and the most common TEAEs were anemia (74%), nausea (57%), fatigue (51%), leukopenia (51%), neutropenia (49%), thrombocytopenia (46%), and vomiting (31%). The most prevalent grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), leukopenia (17%), and fatigue (9 %). Partial responses (PR) were noted in 4 pts (13%); 10 pts (32%) achieved stable disease for > 4 months for a clinical benefit rate (CBR) of 45%. 16 pts (47%) had prior exposure to a taxane, including 1 pt who achieved PR. Among 24 evaluable pts with ovarian cancer, response rate was 17%, CBR was 58%, and PFS was 6.83 months (95% CI 3.73, not reached (NR)). Median duration of clinical benefit in ovarian cancer was 7.57 months (95% CI: 4.43, NR). Conclusions: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity, and further evaluation with once weekly selinexor is warranted. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies. Clinical trial information: NCT02419495.

scholarly journals 531 A Phase 1b multi-tumor cohort study of cabozantinib plus atezolizumab in advanced solid tumors: results of the triple-negative breast cancer, ovarian cancer, and endometrial cancer cohorts

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A562-A562
Author(s):  
Ira Winer ◽  
Akhila Wimalasingham ◽  
Joaquina Baranda ◽  
Armando Santoro ◽  
Kristen Spencer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Endometrial Cancer ◽  
Solid Tumors ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Prior Therapy ◽  
Phase 1B

BackgroundCabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which might enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960), a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in advanced solid tumors; here we present efficacy and safety results in patients with triple negative breast cancer (TNBC), ovarian cancer (OC), and endometrial cancer (EC).MethodsEligible patients had locally advanced or metastatic TNBC, OC, or EC and had radiographically progressed on prior systemic anticancer therapy. One or two lines of prior therapy were permitted. Patients with OC were platinum resistant or refractory. Prior treatment with anti-PD-1 or anti-PD-L1 agents was allowed for patients with TNBC. Patients received cabozantinib, 40 mg PO QD, plus atezolizumab, 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 as assessed by investigator. Other endpoints included safety, duration of response (DOR), progression free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter.ResultsAs of February 19, 2021, 30–32 patients were enrolled in each of the cohorts. 47% of patients with TNBC, 47% with OC, and 40% with EC had received 2 lines of prior therapy. Median follow-up was 18.7 months, 20.8 months, and 19.0 months for the TNBC, OC, and EC cohorts, respectively. Grade 3/4 treatment-related adverse events occurred in 33% of patients with TNBC, 56% with OC, and 37% with EC. One Grade 5 treatment-related adverse event of pulmonary hemorrhage occurred in the TNBC cohort and one of encephalitis occurred in the OC cohort. Cabozantinib plus atezolizumab demonstrated clinical activity in all three tumor cohorts (table 1).Abstract 531 Table 1ConclusionsCabozantinib in combination with atezolizumab demonstrated encouraging clinical activity in patients with previously treated advanced cancers.AcknowledgementsMedical writing support provided by Suvajit Sen, PhD (Exelixis, Inc.)Trial RegistrationNCT03170960Ethics ApprovalYesConsentYes

Phase I expansion cohort trial to investigate the safety and clinical activity of avelumab (MSB0010718C) in patients with metastatic or locally advanced solid tumors.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS3101-TPS3101
Author(s):  
Christopher Ryan Heery ◽  
Jeffrey R. Infante ◽  
Nicholas Iannotti ◽  
Karen Kelly ◽  
Petros Nikolinakos ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Expansion Cohort

A phase 1b/2 study of INCB039110 + nab-paclitaxel (N) and gemcitabine (G) in patients (pts) with advanced solid tumors and pancreatic cancer (PC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 362-362 ◽  
Author(s):  
Gregory Lawrence Beatty ◽  
Safi Shahda ◽  
J. Thaddeus Beck ◽  
Nikhil Premparkash Uppal ◽  
Steven J. Cohen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Cancer Progression ◽  
Malignant Cell ◽  
Primary Objective ◽  
Clinical Activity ◽  
Induction Phase ◽  
Open Label ◽  
Prior Therapy ◽  
Phase 1B ◽  
Grade 3

362 Background: JAK-STAT activity has been associated with malignant cell proliferation and production of proinflammatory cytokines involved in cancer progression. INCB039110 is a potent and selective inhibitor of JAK1. Methods: This was a 2-part phase 1b/2 open-label study evaluating INCB039110 (300 or 400 mg QD) in combination with N and G in pts with advanced or metastatic solid tumors (Part 1 [P1], dose optimization phase) and pts with advanced or metastatic PC who had not received prior chemotherapy (Part 2 [P2] and 2A [P2A]). Pts in P2 received the MTD established in P1: INCB039110 (300 mg QD) + N (125 mg/m2 day [d] 1, 8, 15) + G (1000 mg/m2 d 1, 8, 15), 28-d cycle. For exploratory purposes, pts in P2A underwent a 7-d induction phase with INCB039110 (200 mg QD) before receiving INCB039110 (200 mg QD) + N (125 mg/m2 d 1, 8, 15) + G (1000 mg/m2d 1, 8, 15). The primary objective was to evaluate safety/tolerability. Results: 55 pts were enrolled (27 P1, 20 P2, and 8 P2A). Most patients had advanced PC (n = 46). Median age was 65 (P1), 67 (P2), and 66 years (P2A). Prior therapy: 67% in P1, 30% in P2, and 0% in P2A. The most common reasons for treatment discontinuation were adverse events (AEs; 41% P1, 20% P2, 38% P2A), disease progression (37% P1, 45% P2, 0% P2A), and study termination by the sponsor (0% P1, 0% P2, 38% P2A). Median treatment durations were 84 d (P1), 121 d (P2), and 47 d (P2A). The most common non-hematologic AEs (all grades) were fatigue (59% P1, 75% P2, 88% P2A), nausea (41% P1, 50% P2, 38% P2A), pyrexia (37% P1, 40% P2, 13% P2A), and peripheral edema (30% P1, 50% P2, 25% P2A), with few grade 3 or 4 non-hematologic AEs. The most common grade 3 or 4 hematologic AEs (laboratory values) were neutropenia (33% P1, 60% P2, 13% P2A), lymphopenia (30% P1, 30% P2, 13% P2A), and leukopenia (30% P1, 45% P2, 0% P2A). The most common serious AEs occurring in ≥ 3 pts were pneumonia (n = 4 P1, n = 2 P2, n = 0 P2A) and anemia (n = 3 P1, n = 2 P2, n = 2 P2A). Among evaluable patients, ORR (all PRs) and DCR were 27% (13/48) and 75% (36/48), respectively. Responses were seen across INCB039110 doses. Conclusions: INCB039110 + N/G showed an acceptable safety profile in pts with advanced PC, with the combination demonstrating clinical activity. Clinical trial information: NCT01858883.

Phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of GS-3583, a FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3147-TPS3147
Author(s):  
Joshua Brody ◽  
John A. Thompson ◽  
Anthony W. Tolcher ◽  
Michelle R. Kuhne ◽  
Xi (Rochelle) Huang ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Immunoglobulin G4 ◽  
Phase 1B

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to and activates FLT3 on terminally differentiated DCs. Activated FLT3 promotes proliferation, inhibits cell death, and is required for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. GS-3583 is a fusion protein composed of the extracellular domain of recombinant human FLT3L fused to an engineered fragment crystallizable (Fc) region of human immunoglobulin G4. GS-3583 has PK properties that support sustained cDC in patients and potential combination with established immunotherapies. This phase 1b, open-label, multicenter, dose-finding study will evaluate safety, tolerability, PK, and preliminary efficacy of GS-3583 monotherapy in patients with advanced solid tumors (NCT04747470). Methods: Approximately 33 adults aged ≥18 years with a histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available will be enrolled. The study employs a 3+3 dose escalation design in which GS-3583 is administered intravenously for up to 52 weeks or until progressive disease or unacceptable toxicity. Up to five dose escalation cohorts have been planned. The maximum tolerated dose is the highest dose with incidence of DLT in < 33% of 6 or more patients in the first 28 days of GS-3583 dosing; recommended phase 2 dose will be determined. Assessments include safety, PK, pharmacodynamics including cDCs, immunogenicity, and efficacy by RECIST 1.1 in CT/MRI imaging conducted every 8 weeks. Accrual at approximately 3-4 centers in the US is ongoing. Clinical trial information: NCT04747470.

Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, as monotherapy in non-small cell lung cancer (NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2669-TPS2669
Author(s):  
David S. Hong ◽  
John H. Strickler ◽  
Marwan Fakih ◽  
Gerald Steven Falchook ◽  
Bob T. Li ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Objective Response ◽  
Locally Advanced ◽  
Antitumor Efficacy ◽  
Tolerability Profile ◽  
Molecular Testing ◽  
Open Label ◽  
Eligibility Criteria ◽  
Phase 1B ◽  
Combination Regimens

TPS2669 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRASG12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. The combination of sotorasib with other anticancer therapies may enhance antitumor efficacy. This master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib combinations in patients (pts) with KRASp.G12C mutated solid tumors. Herein, we overview 1 monotherapy and 11 combination cohorts. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens (Table) in pts with advanced KRAS p.G12C mutated solid tumors. Dose exploration will evaluate the safety and tolerability of sotorasib alone and in combination regimens; dose expansion will then verify the safety and tolerability profile of sotorasib regimens and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in pts who have received ≥1 lines of prior systemic therapy. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (eg, objective response, disease control, duration of response, progression-free survival, and duration of stable disease assessed per RECIST 1.1). Enrollment began in December 2019 and is ongoing. Clinical trial information: NCT04185883. [Table: see text]

Safety and efficacy of neoadjuvant pembrolizumab in mismatch repair deficient localized/locally advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2520-2520
Author(s):  
Kaysia Ludford ◽  
Kanwal Pratap Singh Raghav ◽  
Mariela A. Blum Murphy ◽  
Nicole D. Fleming ◽  
Douglas A. Nelson ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Solid Tumors ◽  
Response Rate ◽  
Locally Advanced ◽  
Braf V600e ◽  
Clinical Activity ◽  
Tumor Type ◽  
Organ Sparing ◽  
Grade 3

2520 Background: Pembrolizumab (Pembro), anti-PD1 therapy, is FDA approved for refractory microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) advanced/metastatic solid tumors. The robust activity of anti-PD1 therapy in these tumors argues for a neoadjuvant organ-sparing approach. However, the role of anti-PD1 monotherapy in the neoadjuvant setting is unknown. Methods: This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease per RECISTv1.1 and ECOG PS 0/1. Treatment is Pembro 200mg every 3 wks for 8 cycles (6 months) followed by surgical resection with option to continue therapy for 18 cycles (12 months) followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA [highest variant allele frequency (VAF) baseline mutation]. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery. Results: Between 12/2019 and 2/2021, 32 pts were enrolled and treated. Enrolment goal of 35 anticipated to be met by 4/2021. Baseline characteristics included 13 females, median age of 63 yrs (range 26 - 91), Lynch syndrome in 12 pts, BRAF V600E mutation in 11 pts. Tumor type included 24 CRC and 8 non-CRC (1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, 2 pancreatic). At baseline disease was resectable in 23 (72%). Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1). Only one pt progressed after initial SD of -18%. Median follow-up is 6.1 months (range 0.1 - 14). Among the 6 (20%) pts who underwent surgery, pCR was seen in 3 (50%). A non-operative approach (pembro for 12 months) has been chosen in 15 pts and 1-year organ-sparing was seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events (TRAE) were seen in 3 (9%) pts: grade 3 immune hepatitis (2) and grade 3 type 1 diabetes (1). Baseline ctDNA was positive in 17 (53%) pts with a median of 4 mutations per pt (1 - 35) and median highest VAF of 0.9% (range 0.3% to 38.2%). Among 26 pts with successful tumor tissue testing, median tumor mutations were 10.5, range 1 to 21 (Oncomine 134 gene panel). ctDNA decline at 3 weeks was seen in 14/17 (82%) patients. Luminal disease was present in 24 pts with endoscopic response of: CR in 13 (54%), major response 1, pending follow-up evaluation 6, not evaluated 3, and no response in 1. Conclusions: Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation. Clinical trial information: NCT04082572.

Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS541-TPS541
Author(s):  
Neeraj Agarwal ◽  
Ulka N. Vaishampayan ◽  
Bradley Alexander McGregor ◽  
Marjorie C. Green ◽  
Nehal Mohamed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS541 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

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