scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

Safety, tolerability, and pharmacokinetics (PK) of rilotumumab in Japanese patients (pts) with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 130-130
Author(s):  
Toshihiko Doi ◽  
Rui Tang ◽  
Yilong Zhang ◽  
Elwyn Loh ◽  
Richard Lizambri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Dose Escalation Study

130 Background: Rilotumumab (R) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the only known MET receptor ligand. The MET pathway has been identified as a potentially useful target for therapeutic blockade in oncology. R has been studied in multiple phase 2 trials either as monotherapy or combination therapy, including a phase 2 trial in gastric cancer combining R with epirubicin, cisplatin, and capecitabine. A phase 1 study was done to evaluate the safety, tolerability, and PK of R in Japanese pts. Methods: An open-label, dose-escalation study was performed with R at 10 mg/kg (Cohort 1A), escalating to 20 mg/kg (Cohort 1B) if no dose-limiting toxicities (DLTs) were observed. Key eligibility criteria were Japanese pts with unresectable locally advanced or metastatic carcinoma, age ≥ 20 yr, ECOG ≤ 1, and refractory to standard treatment (tx). Pts received R as an intravenous infusion on days 1 and 15 of each 28-day cycle, except for cycle 1 in which the day 15 dose was skipped to facilitate PK analysis. DLTs were evaluated in cycle 1. Results: A total of 9 pts were enrolled (1A, n = 3; 1B, n = 6). No DLTs were noted. As of 17 April 13, tx-emergent AEs were reported in 89% of pts. Tx-emergent AEs occurring in > 1 pt overall were vomiting (33%), diarrhea (22%), decreased hemoglobin (22%), hypoalbuminemia (22%), and nausea (22%). One grade 3 tx-emergent AE was observed (decreased hemoglobin; 10 mg/kg). Tx-related AEs were reported in 56% of pts. One grade ≥ 2 tx-related AE was observed (hypoalbuminemia; 20 mg/kg). 8 pts discontinued R due to disease progression; 1 pt remained on the investigational product. Mean exposure of R (Cmax and AUC) appeared to be doubled as dose increased from 10 to 20 mg/kg. The estimated mean CL was approximately 0.2 mL/hr/kg in both cohorts, suggesting a linear PK from 10 to 20 mg/kg. The terminal half-life of R was about 15 days. Conclusions: R monotherapy had an acceptable safety profile in Japanese pts with advanced solid tumors. These phase 1 safety and PK data support the further evaluation of R combined with chemotherapy in Japanese pts with MET-positive metastatic gastric cancer. Clinical trial information: NCT01791374.

A first-in-human phase dose-escalation study of YH002, a recombinant humanized agonistic anti-OX40 IgG1 monoclonal antibody, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Kate Wilkinson ◽  
John J. Park
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Cancer Breast ◽  
Dose Levels

e14501 Background: YH002 is a recombinant humanized IgG1 antibody that targets the human OX40 receptor. Preclinical studies have demonstrated the specificity, potency, and anti-cancer efficacy of YH002 in a comprehensive panel. The totality of nonclinical data supports progression of YH002 into clinical studies in adult patients (pts) with advanced solid tumors. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced or metastatic refractory solid tumors received YH002 as single agent by IV administration at 0.01 to12.0 mg/kg dose levels every 21 days (Q3W), to evaluate the safety, tolerability and preliminary efficacy. An accelerated titration dose escalation design followed by a traditional 3+3 dose algorithm were utilized to assess dose-limiting toxicity (DLT) and identify MTD and/or RP2D. Tumor assessments were performed per RECIST v1.1 every 9 weeks. Results: By December 31 2020, six patients were enrolled and treated at escalating dose levels of 0.01 (n=1), 0.03 (n=1), 0.1 (n=1) and 0.3mg/kg (n=3), with tumor types including colon cancer, thymic cancer, prostate cancer, colorectal cancer, breast cancer and bladder cancer. Median treatment duration was 10.2 weeks (range 2 – 18). The median age of patients was 67 years old (range 47-78). These patients had progressed after a median of 2 prior lines of available standard therapy. As of data cutoff, no dose limiting toxicities (DLTs), no Grade (G) 3 or above adverse events (AE) or AEs leading to treatment discontinuation were reported. Drug-related adverse events (AEs) were all G1/2 events and occurred in 4 patients, including 8 G1 AEs (pneumonitis, rash, pruritus, arthralgia, myalgia, fatigue, lethargy, rash pruritic) and 3 G2 AEs (1 pneumonitis and 2 fatigue). Out of 5 patients having tumor assessment by RECIST, one pt with Thymic SCC at 0.3 mg/kg had best response of stable disease at week 9, one pt with prostate cancer at 0.1 mg/kg experienced Non-CR/Non-PD, and rest of 3 pts experienced progressive disease. Conclusions: These preliminary results demonstrate that YH002 was safe and tolerable up to 0.3mg/kg. Updated safety and antitumor activity will be presented. Clinical trial information: NCT04353102.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3586-3586
Author(s):  
Ignacio Garrido-Laguna ◽  
Patrick Michael Dillon ◽  
Stephen Patrick Anthony ◽  
Margit Janat-Amsbury ◽  
Nissa Ashenbramer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

scholarly journals A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

2020 ◽  
Author(s):  
Toshihiko Doi ◽  
Masaomi Tajimi ◽  
Joji Mori ◽  
Hiroya Asou ◽  
Koichi Inoue ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Japanese Patients ◽  
Primary Objective ◽  
Pharmacokinetic Parameters ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Summary Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW. Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016.

A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2577-2577
Author(s):  
Vinod Ganju ◽  
Adam Cooper ◽  
Bo Gao ◽  
Kate Wilkinson
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Gastroesophageal Junction Cancer ◽  
Anti Cancer ◽  
Ongoing Phase

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.

Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: A phase I/II trial in progress.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3146-TPS3146
Author(s):  
Jayesh Desai ◽  
Tarek Meniawy ◽  
Brandon Beagle ◽  
ZheZhen Li ◽  
Song Mu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Response ◽  
T Cell ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Tumor Types

TPS3146 Background: While immune surveillance plays a critical role in preventing tumor proliferation and metastasis, tumors develop resistance mechanisms to suppress and/or escape the immune system. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and programmed cell death protein-1 (PD-1) function as immune checkpoint receptors on tumor-infiltrating lymphocytes. Overlap in expression and function suggests TIM-3 and PD-1 cooperate to maximize effector T-cell exhaustion, leading to a decreased antitumor immune response. Although blockade of TIM-3 alone is unlikely to result in an efficacious antitumor immune response, combined TIM-3/PD-1 blockade may enhance the antitumor properties of anti-PD-1 therapies alone. BGB-A425 is an investigational IgG1-variant monoclonal antibody against TIM-3. Tislelizumab, an anti-PD-1 antibody, was engineered to minimize binding to FcɣR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This phase 1/2 study will assess the safety/tolerability, pharmacokinetic (PK) profile, and antitumor activity of BGB-A425 in combination with tislelizumab in patients with advanced solid tumors. Methods: This is an open-label phase 1/2 study (NCT03744468) of BGB-A425 in combination with tislelizumab in patients with histologically/cytologically confirmed advanced, metastatic, unresectable solid tumors. Phase 1 will determine the recommended phase 2 dose (RP2D) for combination treatment; phase 2 will assess the antitumor effects of the combination in select tumor types. In phase 1, up to 42 patients will be enrolled into sequential cohorts of increasing doses of intravenous (IV) BGB-A425 in combination with tislelizumab 200 mg IV, based on a 3+3 study design. During Cycle 1, patients will receive BGB-A425 alone on Day 1 followed by tislelizumab alone on Day 8. If no dose-limiting toxicities are observed, patients will receive both BGB-A425 and tislelizumab sequentially on Day 29 and every 21 days thereafter. Once the RP2D is determined, the combination therapy will be evaluated in up to 120 patients with select tumor types in phase 2. Safety/tolerability profile and RP2D determination (phase 1) and objective response rate per RECIST v1.1 (phase 2) are primary objectives; secondary objectives include antitumor activity, PK profile, and immunogenicity of combination therapy. Clinical trial information: NCT03744468 .

KRYSTAL-2: A phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS146-TPS146
Author(s):  
Joshua K. Sabari ◽  
Haeseong Park ◽  
Anthony W. Tolcher ◽  
Sai-Hong Ignatius Ou ◽  
Edward B. Garon ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Human Tumor ◽  
Mapk Signaling ◽  
Cellular Growth ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.

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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