G3 Diarrhea Research Articles

Beamion LUNG-1, a Phase Ia/Ib trial of the HER2-specific tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with HER2-driven tumors: outcomes according to HER2 aberration type

Abstract Introduction/Objective Beamion LUNG-1 (NCT04886804) is an ongoing, Phase Ia/Ib trial evaluating the novel HER2- specific tyrosine kinase inhibitor, zongertinib, in patients with HER2 aberration-positive solid tumors (Phase Ia) and HER2 mutation-positive NSCLC (Phase Ib). Here, we report data from Phase Ia according to HER2 aberration type. Methods/Case Report Phase Ia enrolled patients with HER2 aberration-positive (by local assessment: gene mutations, rearrangements, amplification, or overexpression) advanced/metastatic solid tumors. Patients received escalating doses of zongertinib BID (≥15 mg) or QD (≥60 mg), guided by a Bayesian model with overdose control. The primary endpoint of Phase Ia was maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Results (if a Case Study enter NA) At data cut-off (January 29, 2024), 83 patients received zongertinib (BID n=17; QD n=66). Three patients had DLTs during the MTD evaluation period (G3 decreased platelets, G3 diarrhea, G4 neutropenia); the MTD was not reached. Treatment-related adverse events (TRAEs; all/G3/G4/G5) were reported in 76%/8%/1%/0% of patients. Confirmed investigator-assessed ORR/DCR rates in evaluable patients/patients with NSCLC (n=74/n=41) were 35%/85% and 44%/93%; median duration of response was 12.7/15.8 months, respectively. Based on preliminary data, 43 patients were HER2 mutation-positive (TKD/non-TKD/unknown n=36/n=6/n=1; A775_G776insYVMA n=16; G778dupGSP insertions n=3; S310F n=2); 23 patients overexpressed HER2 (2+/3+); 17 had HER2 amplification; 3 patients had NRG1 fusions. ORR/DCR rates (regardless of confirmation) in patients with TKD mutation-positive, A775_G776insYVMA-positive, non-TKD mutation-positive, G778dupGSP-positive and S310F- positive tumors were 64%/97%, 69%/94%, 20%/100%, 33%/100% and 50%/100%, respectively. ORR/DCR rates (regardless of confirmation) in patients with HER2 overexpressing tumors (+/- amplification) were 39%/83%. Of the 3 patients with NRG1 fusions, one had a partial response and two had stable disease. Conclusion In this preliminary analysis, zongertinib showed promising activity across a broad range of tumor types with different HER2 aberrations, including aberrations that have historically been difficult to treat. Updated data will be presented.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

Safety and efficacy of intensified preoperative management of locally advanced gastrorsophageal junction cancer (INPROVE).

e16110 Background: The optimal management of locally advanced gastroesophageal junction adenocarcinoma (LAGEJad) is not fully established yet. Both neoadjuvant chemoradiotherapy (CRT) and perioperative taxane-based triplet chemotherapy (CT) are acknowledged treatment options for Siewert I and II cancers. In this retrospective study, we aimed to assess the safety and outcomes of an intensified preoperative regimen combining taxane-based triplet CT and CRT. Methods: We conducted a retrospective analysis of a cohort comprising 16 consecutive HER2 negative patients (pts) with LAGEJad treated at the Centro di Riferimento Oncologico of Aviano between 2019 and 2022. All pts received induction CT (iCT) consisting of fluoropyrimidine, oxaliplatin and docetaxel, followed by CRT (45Gy/25Fr) with simultaneous boost and concomitant CT. Surgery (Ivor-Lewis or McKeown) was performed 8 weeks post-CRT. Clinico-pathological (CP) and treatment features were analyzed using logistic regression to assess their association with response to iCT-CRT. The association of iCT-CRT with survival outcomes was investigated using the Kaplan-Meier method. Results: Key CP data are summarized in Table 1. Median age was 59 years, all pts were male. At diagnosis, 81.2% of pts exhibited cT3+ and cN+ disease. All pts received iCT and CRT. The rate of partial responses was 50% after iCT and 68.8% after CRT. Overall, 12 pts underwent surgery, all achieving R0 resections within a median timeframe of 9 [8.5;11] weeks post-CRT. Among them, 25% had a pathologic complete response, while 62.5% attained a Mandard tumor regression grade (TRG) of 1-2. No new safety signals emerged from iCT (only 2 pts had ≥G3 diarrhea) or CRT (≥G3 mucositis occurred in 6.2% and anemia in 6.2% of pts). No significant surgical delays were observed, although 5 pts experienced post-operative complications (4 grade I, 1 grade IIa). There were no statistically significant associations between CP variables and response to the iCT-CRT. Relapses were seen in 8 pts (2 locoregionally); 3-year survival was 46%. Median event-free survival was 5 [5;11] months, while median overall survival 34 [14;NR] months. Conclusions: The intensification of preoperative treatment in pts with LAGEJad is active and safe: the surgical schedule was not significantly delayed, and the safety profile remained comparable to standard regimens, with no major complications reported. Randomized clinical trials are ongoing to assess the clinical benefits of this approach. [Table: see text]

Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients (pts) with advanced solid tumors: A phase 1/2 trial.

3014 Background: Dendrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC). Methods: Pts who had exhausted standard therapy were enrolled in dose assessment (P1)/dose expansion (P2) cohorts of DEP SN38 given IV 3-weekly (Q3W) or Q2W alone or in combination with 5-fluorouracil & leucovorin (5FU/LV combo). Efficacy was evaluated by RECIST 1.1 and serum tumor markers. (EudraCT 2019-001318-40). Results: 114 pts were enrolled. The Q3W Recommended Dose (RD) was 12.5 mg/m2 SN38 with dose limiting toxicity (DLT) in 1/7 pts (grade (G) 4 neutropenia > 7d). The Q2W RD was 12.5 mg/m2 for SN38 alone or with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens with mostly mild/moderate (G1/2) treatment-related adverse events (TRAEs) & no new events compared with c-IRI. TRAEs in ≥ 10% pts included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, diarrhea, constipation and alopecia. Of734 DEP SN38 cycles only 1 event of G3 diarrhea (0.9% pts) and no cholinergic symptoms have been observed, contrasting with c-IRI (~20% & 47% pts respectively). G3 nausea (1.8% pts) and vomiting (0.9% pts) occurred less frequently than with c-IRI (both ~10% pts). Febrile neutropenia was the DLT at 15 mg/m2 Q2W monotherapy (2/6 pts), with neutropenia otherwise essentially uneventful and managed with G-CSF. 38 CRC pts received DEP SN38 monotherapy (31 evaluable) and 17 received the 5FU/LV combo (14 evaluable). CRC pts had a mean 4 prior lines with 97% receiving ≥ 1 c-IRI containing line. The disease control rate (DCR) in monotherapy was 48% (stable disease (SD) up to 72 wks). The 5FU/LV combo cohort DCR was 85.7%, the objective response rate (ORR) was 14.3%, with disease control observed for at least 35 wks. Several CRC pts continue combo treatment. 23 HGSOC pts with a mean of 6 prior lines received DEP SN38 monotherapy (18 evaluable). The DCR for Q2W was 100% with 33.3% ORR, and 72% DCR for all HGSOC pts. 3 pts have PRs for at least 36 wks; with 1 pt achieving complete tumor & ascites resolution. Reduced CA-125 of up to 98% was observed in 75% pts. Several HGSOC pts continue DEP SN38 treatment. 8 BC pts with a mean of 7 prior lines received DEP SN38 monotherapy Q3W (5 evaluable). The DCR was 100% with SD up to 72 wks. Conclusions: DEP SN38 shows promising clinical utility with encouraging antitumor activity including prolonged disease control & durable PRs in heavily pre-treated CRC, HGSOC & BC pts. DEP SN38 is well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to c-IRI, & warrants further clinical assessment. Clinical trial information: 2019-001318-40 .

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial

PurposeTo evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. MethodsIn this phase III, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiotherapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiotherapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiotherapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea; ≥G1 and ≥G2 diarrhea lasting at least 3 days; and damage to the rectal mucosa due to radiotherapy measured by endoscopy. ResultsTwo-hundred-and-eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 140). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs. 14.8 and 4.5 days, respectively; P<0.001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs. 55.7%, P<0.001). Three patients felt intolerable or abdominal pain following rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P=0.061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P<0.001). ConclusionThe results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody) in combo with pembrolizumab (Pembro) in patients (Pts) with metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

127 Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody that has a cleavable masking peptide that blocks the antigen binding site. ADG126 is preferentially activated in the tumor microenvironment to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. Activated ADG126 binds to a unique CTLA-4 epitope to prime T cells via partial ligand blockade and deplete immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC)/phagocytosis (ADPC). Preclinical studies showed that ADG126/Pembro combination effectively increases Teff/Treg ratio. In Phase 1b/2 studies, ADG126 demonstrated a favorable safety profile and clinical efficacy as monotherapy and in combination with anti-PD-1 therapy. Here we present results of the entire dose escalation and ongoing dose expansion cohorts including a cohort of patients with MSS CRC free of liver metastasis (NCT05405595). Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study of ADG126/Pembro. Pts received ADG126 [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1. Results: As of Aug 29, 2023, a total of 47 Pts have been treated in dose escalation (N=11) and expansion cohorts (N=36). The median age is 60.5 yrs (26-78); 31.9% Pts had at least 3 prior therapies, 12.8% Pts received prior IO therapies. A majority of Pts (74.5%) have what are considered immunologically “cold” tumors. ADG126 was dosed at 6 mpk Q6W (1 Pt) and Q3W (5 Pts), 10 mpk Q6W (17 Pts) and Q3W (24 Pts), and Pembro was dosed at 200 mg Q3W. No DLT or Grade 4/5 TRAE was observed at any dose level. TRAEs more than 10% are pruritis (N=9, 19.1%) and diarrhea (N=5, 10.6%). Grade 3 TRAEs were observed in 5 subjects: 1 G3 diarrhea (6 mpk, 16.7%), 1 G3 adrenal insufficiency (10 mpk Q6W, 5.9%), 1 each G3 pancreatitis, blurred vision and lipase increase (10 mpk Q3W, 12.5%); all TRAEs occurred after repeat dosing. For the MSS CRC expansion cohort, 7 SDs at ADG126 10 mpk Q6W dose level (N=11) were observed, and 2 PRs (including 1 initial PR) and 4 SDs at 10 mpk Q3W (N=13) were observed. Conclusions: ADG126/Pembro combination is well-tolerated up to the maximally administered dose of 10 mpk Q3W, with limited G3 TRAEs comparable to Pembro monotherapy. The 10 mpk ADG126 Q3W repeat dosing regimen maintains a favorable safety profile and demonstrates anti-tumor activity. The MSS CRC cohort of 10 mpk ADG126 Q3W surpassed the threshold set for part 1 of the Simon’s 2-stage design, and the second stage of the cohort is now enrolling. In conclusion, ADG126/Pembro has a significantly improved therapeutic index over the same class agents in combination with anti-PD-1 therapy, and encouraging early outcomes in patients of MSS CRC without liver metastasis. Clinical trial information: NCT05405595 .

Zanubrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) for Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results from a Phase 1b Clinical Trial

Introduction. Although most patients (pts) with DLBCL are cured with R-CHOP, ~40% develop refractory or relapsed disease. Several studies have shown a potential therapeutic role for BTK inhibitors in DLBCL. In the phase 3 PHOENIX trial of pts with DLBCL, the addition of ibrutinib to R-CHOP failed to improve overall outcomes. However, in pts &amp;lt;60 years, ibrutinib plus R-CHOP improved the progression-free (PFS) and overall (OS) survivals. The age-based difference in outcomes with ibrutinib plus R-CHOP may be due to greater toxicity and reduced R-CHOP dose intensity with this combination in older pts. We hypothesized that zanubrutinib, a 2 nd-generation BTK inhibitor with greater selectivity for BTK and improved safety compared with ibrutinib, could be safely combined with R-CHOP and improve outcomes. Methods. This phase Ib investigator-initiated trial is being conducted at 2 US centers. Eligible pts had previously untreated DLBCL, stage II-IV, and International Prognostic Index (IPI) score ≥1. Pts received standard-dose R-CHOP on day 1 and zanubrutinib on days 1-21 for six 21-day cycles. A dose de-escalation design was used to determine the recommended phase 2 dose (RP2D) followed by an expansion cohort. One cycle of R-CHOP off protocol was permitted. Primary prophylaxis with G-CSF was not mandated and followed national guidelines. The primary objective was to determine the RP2D and safety of zanubrutinib plus R-CHOP (ZaR-CHOP). Secondary objectives included overall response rate (ORR), PFS and OS for pts treated at the RP2D, and descriptive data on treatment exposure to zanubrutinib and R-CHOP. Interim results of pts treated with ZaR-CHOP are presented here. Results. From 10/2021 to 5/2023, 16 pts signed consent of whom 2 were ineligible. Data for the 14 eligible and safety-evaluable pts are shown here. The median age was 59 years (range 23-74) and 4 pts (29%) were ≥65 years. Ten pts (71%) had stage IV, 9 (64%) elevated LDH, 6 (43%) high-intermediate or high IPI, and 7 (50%) had bulky (≥10 cm) disease (missing n=3). Cell-of-origin by Hans was germinal center (GC) in 7 pts (50%) and non-GC in 7 (50%); 5 pts (38%) had double-expressor DLBCL (MYC ≥40% and BCL2 ≥50% by immunohistochemistry) (missing n=1). No dose-limiting toxicities occurred and zanubrutinib 160 mg twice daily was selected as the RP2D. Two pts withdrew from trial (1 pt after cycle 5 in the setting of recurrent/persistent COVID19 infection and 1 pt after cycle 2 due to grade (G) 2 stomach pain and G1 diarrhea); both were able to receive 6 cycles of R-CHOP. No dose reductions in cyclophosphamide or doxorubicin occurred. One pt required zanubrutinib dose reduction for febrile neutropenia (FN). The most frequently reported (≥30%) all-grade treatment-emergent adverse events (TEAEs) were lymphopenia 79%, fatigue 57%, leukopenia 50%, sensory peripheral neuropathy 50%, anemia 43% (G1 14%, G2 14%, G3 14%), thrombocytopenia 43% (all G1), hyperglycemia 43%, cough 43%, diarrhea 36% (all G1), nausea 36% (G1 29%, G2 7%), elevated alanine aminotransferase 36% (all G1), neutropenia 36%, hyponatremia 36% (G1 29%, G2 7%), and alopecia 36% (Table). The most frequently reported (≥10%) G≥3 TEAEs were neutropenia 29%, lymphopenia 29%, leukopenia 21%, anemia 14%, and FN 14% (no G4). The most frequently reported serious adverse event (AE) was FN (3 pts (21%) each with 1 G3 event, including 1 event after standard-of-care cycle 1 R-CHOP and 1 after off-protocol cycle 6 R-CHOP in a pt who withdrew from trial). One pt developed G4 sepsis that resolved without sequelae. Bleeding AEs were limited to hematuria (21%, all G1) and bruising (14%, all G1), and cardiac AEs to palpitations (7%, G1). Twelve pts were evaluable for response; 1 pt remains on treatment and 1 awaiting response assessment. The ORR was 91.6% (95% confidence interval 61.5-99.8%) including complete response (CR) in 83.3% and PR in 8.3% (2 pts had positive end-of-treatment (EOT) PET but declared CR based upon follow-up PET and/or biopsy). One pt had progressive disease on EOT PET. With a median follow up of 4.3 months (range 0-15 months) from EOT response assessment, no relapses or deaths occurred on study. Conclusion. The addition of zanubrutinib to R-CHOP is well tolerated and does not compromise R-CHOP delivery. Given the recent approval of polatuzumab in combination with R-CHP in DLBCL, and no additional toxicity concerns identified in this phase Ib trial, the protocol is being amended to substitute polatuzumab for vincristine.

Updated results of the phase 1 I-FLOAT trial: Safety and efficacy of combining genotype-guided irinotecan with 5FU, leucovorin, oxaliplatin and docetaxel (gFOLFOXIRITAX) in advanced upper GI cancers.

e16038 Background: 5FU, Oxaliplatin (ox), irinotecan (iri) and docetaxel (tax) are each active in upper GI cancers; however, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms may predispose to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of therapy (tx) among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. We report the updated results of the I-FLOAT trial. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and H risk groups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu &amp; Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1) &amp; ctDNA response (&gt;50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-1/1/2023, 27 pts (11F, 16M) enrolled: median age 51 (range 21-76); 9 ECOG PS 1, UGT-L:I:H with 6:18:3 pts; 12 esophageal, 6 gastric, 8 pancreatic, and 1 bile duct cancer; 3 pts HER2+; 22 metastatic, 5 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.2-4.7) and 4.06 (1.89-27.6), respectively; 81% (22/27) of pts had a NLR &gt; 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 5 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax), one G3 fatigue (UGT-I DL2/DL2 Iri/Tax) and one G3 diarrhea and neutropenic fever (UGT-L DL4/DL1 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, &amp; UGT-L DL4/DL1. The most frequent any Gr tx related toxicities: diarrhea (78%), fatigue (74%), nausea (70%), neuropathy (67%), anorexia (52%), elevated LFT (48%), anemia (37%), vomiting (37%). Of evaluable pts across all cohorts, PR/CR was seen in 18/22 (82%) patients, with 2 (9%) SD and 2 (9%) PD for a disease control rate of 91%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX continues to demonstrate tolerability at initial DLs of Iri/Tax. Efficacy is promising and could be an aggressive approach in upper GI cancers with high relapse risk in curative-intent settings. Clinical trial information: NCT04361708 .

Interim results from a phase I/II study of duvelisib PI3Kδγ inhibitor and nivolumab in patients with advanced unresectable melanoma who have progressed on anti-PD1 therapy.

9540 Background: The majority of unresectable melanoma patients eventually progress on first-line checkpoint blockade therapy. Duvelisib is a potent phosphoinositide 3-kinase (PI3K) δ and γ isoform inhibitor approved for relapsed/refractory CLL. PI3Kγ inhibition has been shown to restore anti-PD1 activity in preclinical tumor models through conversion of tumor associated macrophages (TAMs) from an immunosuppressive to a pro-inflammatory state. PI3Kδ inactivation has been associated with impaired T regulatory cell (Treg) function and reduced intratumoral Treg numbers. We report study design and results of a phase I study to evaluate the safety and efficacy of duvelisib and nivolumab in anti-PD1 refractory patients. Methods: Utilizing a modified 3+3 design with escalating doses of duvelisib (15 mg daily, 25 mg daily, and 25 mg BID), patients with unresectable melanoma were treated with nivolumab and duvelisib until unacceptable toxicity or disease progression. Primary endpoints for the phase I portion were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of duvelisib. Secondary endpoints include early and late toxicities and anti-tumor activity based on RECIST v1.1. Exploratory endpoints were to evaluate dose-dependent changes in the immune cell populations of peripheral blood and tumor tissue with duvelisib and nivolumab. Results: Ten patients have been enrolled (7 at dose level I, 3 at dose level II) with mean age 64. Two patients had BRAF V600E mutation and were previously treated with BRAF/MEK inhibitors. No dose limiting toxicities (DLT) were observed. Grade 3 or higher adverse events (AEs) attributable to study treatment occurred in 4 patients (40%), including G3 neutropenia (10%), G3 diarrhea (10%), G3 vomiting (10%) and G4 hepatitis (20%). Both instances of hepatitis resolved rapidly with 1-2mg/kg of prednisone. In one patient, hepatitis and nausea/vomiting led to discontinuation of treatment. Out of 6 patients who had follow-up imaging, 4 exhibited progressive disease, one stable disease, and one had partial response of 11 months duration. Given the published data on the regulation of macrophages and Tregs by PI3Kδγ inhibitors, we are utilizing multispectral imaging to measure the spatial interactions of key immune cells within the tumor microenvironment (T cells, B cells, and macrophages) in all matched pre-/post-treatment paraffin-embedded tissues, for which results will be presented. Conclusions: The combination of duvelisib and nivolumab was well-tolerated in patients with advanced unresectable melanoma refractory to ICI without DLTs to date at 15 and 25mg daily dosages. Significant anti-tumor activity was noted in one patient. Enrollment at dose level II is ongoing. Clinical trial information: NCT04688658 .

First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.

3010 Background: PF-07104091 is a novel CDK2-selective inhibitor under investigation in pts with selected advanced or metastatic solid tumors. We present the first disclosure of data from the first-in-human, multicenter, phase 1 study of PF-07104091 monotherapy (NCT04553133). Methods: Pts with HR+/HER2- advanced/metastatic breast cancer (mBC) who received ≥ 2 lines of treatment for mBC including prior endocrine therapy (ET) + CDK4/6 inhibitors (CDK4/6i), and pts with other solid tumors, were included. Prior therapy with fulvestrant and chemotherapy was allowed for pts with mBC. PF-07104091 (75-500 mg) was given twice daily (BID) orally in 28-day cycles, following Bayesian design with overdose control, to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics and preliminary anti-tumor activity. Results: At data cut off (Aug 23, 2022), 35 pts with advanced solid tumors (n = 29 mBC) with median age 62y (range 32-80y), median 4 lines of prior systemic therapy (range 1–12) and ECOG PS 0 (20% pts) or 1 were enrolled. Of 29 pts with mBC, all had prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. Treatment-emergent adverse events (TEAEs) were observed in 34 pts (97.1%; 20 [57.1%] grade [G] ≥ 3). The most frequent TEAEs (all G≤3) were nausea (77.1%; 14.3% G3), diarrhea (48.6%; 8.6% G3), vomiting (48.6%; 2.9% G3), fatigue (45.7%; 20.0% G3) and anemia (45.7%; 8.6% G3). Dose-limiting toxicity occurred in 5 pts: 1 pt (G3 fatigue) at 300 mg BID; 2 pts (1 G3 nausea and G3 anorexia, 1 G3 nausea) at 375 mg BID, and 2 pts (1 G3 fatigue and 1 G3 diarrhea) at 500 mg BID. Steady-state PF-07104091 plasma exposures increased proportionally with dose. A trend of early decrease in ctDNA was observed. Further pharmacodynamic studies are ongoing. PF-07104091 300 mg BID was identified as the MTD and selected as the monotherapy RDE. Among 16 response evaluable mBC pts (all prior CDK4/6i+ET) with measurable disease at baseline, confirmed RECIST v1.1 partial responses were observed in 3 (18.8 %) pts (2 pts with duration of response &gt; 6 months and 1 ongoing at data cut off), and stable disease in 6 (37.5%) pts. Disease control rate was 61.5% in mBC pts (response evaluable set, 95% CI: 40.6, 79.8). Conclusions: Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133 .

Phase 1/2 study of XTX101, a masked, tumor-selective Fc-modified anti-CTLA4, in patients with advanced solid tumors.

e14685 Background: XTX101 is a tumor-selective, anti-CTLA-4 monoclonal antibody (mAb) engineered with covalently linked peptides that mask CTLA-4 antigen-binding regions. The masking peptides are cleaved by matrix metalloproteases that are more active in the tumor microenvironment (TME) compared with healthy tissues. XTX101 is designed with 2 Fc domain mutations (S239D and I332E) which enhance binding to Fcγ receptors and are intended to improve effector function, resulting in depletion of regulatory T-cells in the TME. In a murine model, XTX101 at 0.3 mg/kg achieved similar tumor growth inhibition as 3 mg/kg of an ipilimumab analog, suggesting higher relative potency of XTX101 over ipilimumab (Powderly SITC 2021). Methods: Interim results of first-in-human, Phase 1 portion of study XTX101-01/02-001 (NCT04896697) are reported here. Part 1A examines XTX101 monotherapy in 3+3 dose escalation. Part 1B is evaluating pharmacodynamic (PD) biomarkers. Results: As of January 27, 2023, 22 patients (pts) with advanced solid tumors were enrolled including colorectal (n = 3), pancreatic (n = 3), non-small cell lung (n = 3), squamous cell skin (n = 2), breast (n = 2), uterine (n = 2), cervical, prostate, Fallopian tube cancer, leiomyosarcoma and Merkel cell carcinoma in Part 1A, and melanoma and colorectal cancer in Part 1B. Pts had a median of 3 prior lines of therapy (1-10). Dose levels (DL) of 7, 20 and 60 mg every 3 weeks (Q3W) were cleared (1 dose limiting toxicity (DLT) of colitis among 8 patients treated at 60 mg Q3W), while 2 DLTs of colitis were reported among 6 pts at 180 mg Q3W. An alternative dosing schedule of 150 mg every 6 weeks (Q6W) was implemented based on clinical and pharmacokinetic (PK) data, and no DLTs were reported among 5 pts at this alternative schedule. There were no grade (G) 4 or 5 treatment-related (TR) adverse events (AEs) on the study. G3 TRAEs included colitis (n = 4), infusion reaction (IR, n = 3) and lymphopenia (n = 2). There were no skin, endocrine or liver-related TRAEs of any grade. One patient with squamous cell lung cancer treated at 150 mg Q6W dose had an unconfirmed partial response and continues on treatment. PK exposure with 150 mg Q6W schedule were comparable to 2 cycles of 60 mg Q3W. Among 8 pts treated at 60 mg Q3W and 5 treated at 150 mg Q6W, 2 out of 13 patients (15%) experienced G3 colitis, 1 pt G2 colitis and 1 pt G2 diarrhea. All colitis AEs improved with immunosuppression and resolved. There were 2 IRs at 60 mg Q3W, while no IR occurred with the Q6W schedule. Based on the totality of clinical and PK data, 150 mg Q6W is the recommended Phase 2 dose (RP2D), and enrollment in part 1B is ongoing at this dose. Conclusions: XTX101 is a Fc-engineered, masked, tumor-activated, anti-CTLA-4 mAb in development for advanced solid tumors. At RP2D, the preliminary safety profile is differentiated from systemically active anti-CTLA4 mAb. Updated clinical data, PK, immunogenicity and PD data from the study will be presented. Clinical trial information: NCT04896697 .

A phase I trial of palbociclib (palbo) and bosutinib (bos) with fulvestrant (fulv) in patients (pts) with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) refractory to an aromatase inhibitor (AI) and a CDK4/6 inhibitor (CDK4/6i).

1079 Background: Standard therapy for HR+/HER2- MBC includes a CDK 4/6i with endocrine therapy (ET). Eventual resistance results in progression of disease (PD). A potential mechanism of CDK4/6 resistance is through Src activation. Targeting Src and ET suppresses proliferation of ER+ hormone independent breast cancer cells. Therefore, adding bos, a Src inhibitor, to palbo + fulv may overcome this resistance and restore sensitivity to CDK4/6i. Methods: This is a single arm, 3+3 dose escalation phase I trial (NCT 03854903) of bos + palbo + fulv for pts with HR+/HER2- MBC who have PD after ≥ 1 AI, ≥ 1 CDK4/6i, and &lt; 3 lines of chemo for MBC. Pts were enrolled in two cohorts, A and B, with two dose levels in cohort B. Fulv was given at standard dose. Cohort A: bos 300mg (D1-5/wk), palbo 75mg D1-21 q28 days, fulv; cohort B1: bos 300mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv; cohort B2: bos 500mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv. Primary objective was safety and tolerability, including MTD and recommended phase 2 dose (RP2D). Secondary objectives included ORR, and CBR 24 wks. Serum, plasma, and peripheral blood mononuclear cells were collected for Src activation, cell cycle profile arrays, and cytokine array screens. Results: 18 evaluable pts were enrolled between 4/2019 – 11/2022. To date, 16pts have completed and 2 pts remain on treatment. All pts had received prior palbo and 15/18 (83%) had received prior fulv. Median number of prior therapies in the metastatic setting was 3.2. The combination in cohort A and B1 was well tolerated. The combination in cohort B2 (bos 500mg D1-D5/wk) was toxic which resulted in bos dose reduction in all pts in the B2 cohort. There were no DLTs. The RP2D was bos 300 mg D1–5/wk, palbo 100 mg D1-21 q28 days, and standard dose fulv. No pts came off treatment due to adverse events (AEs). Most common AEs were G1/2 (9 pts) and G3/4 (7 pts) neutropenia (no neutropenic fever); G1 nausea (8 pts); G1/2 (12pts) and G3 (1pt) diarrhea; G1/2 rash (4 pts), and no G5 events. Median PFS was 5.9 months with 95% CI (3, 10.1). CBR at 6 months was 50% (9/18) (95% CI (0.26, 0.74)). The ORR was 6% (0 CR, 1 PR cohort B2), but best response was SD in 11 pts. Correlative studies underway include assessment pre and post treatment of 1) Src levels and activity to confirm that bos is acting on target and 2) RNA sequencing of Src activation and cell cycle profiles and 3) cytokine array screens to test if Bos affects inflammatory markers. Conclusions: Bos + palbo + fulv was well tolerated at the RP2D. A robust CBR of 50% was seen despite all patients having prior PD on palbo and 83% on fulv. This is an effective combination for HR+/HER2- MBC which warrants further investigation and may represent a mechanism to overcome resistance to CDK4/6i and provide another oral treatment option. Clinical trial information: NCT03854903 .

Real-life use of cabozantinib as front-line therapy in metastatic renal cell carcinoma: The CabFRONT (Meet-URO 24) study.

e16539 Background: Cabozantinib is approved as first-line therapy for patients with intermediate-poor risk metastatic renal cell carcinoma (mRCC); however translating results from pivotal trials to an unselected real-world population remains a concern. Methods: CabFRONT is a retrospective observational multicentre Italian Network for Research in Urologic-Oncology (Meet-URO) study of a real-life population of treatment-naïve patients with intermediate-poor mRCC treated with cabozantinib as per clinical practice between September 2019 and September 2022. Results: 209 patients were enrolled. Median age was 65 years (36 - 85). 158 patients (76%) started with a dose of 60 mg, while 51 (24%) started with a dose of 40 mg. 140 patients (67%) were classified as intermediate and 69 (33%) as poor risk according to IMDC risk model. Clear-cell represented the most common histotype (172/209), followed by papillary (19/209), chromophobe (6/209) and NOS (4/209). Sarcomatoid features were present in 29 patients (14%). Lungs were the most frequent metastatic site, [137 (65%) patients], followed by lymph nodes [115 (55%)], and bones [72 (35%)]. 33 (16%) patients presented brain metastases. At a follow-up of 23 months (mo), the median progression-free survival (mPFS) was 9.6 mo (95% CI, 7.63-10.9 mo) and the median overall-survival was 21 mo (95% CI, 14-30 mo). As best overall response, 7 patients achieved a complete response, 73 a partial response and 77 stable disease for an objective response rate (ORR) of 38% and a disease control rate (DCR) of 75%. ORR for intermediate and poor population was respectively 29% and 10%, DCR was 56% for intermediate risk and 20% for poor risk population. mPFS for intermediate and poor population was respectively 12.73 and 5.27 mo (p &lt; 0.0001). mPFS for intermediate with 1 risk factor was 17.2 and for intermediate with 2 risk factors was 9.7 mo (p 0.0033). Subsequent antineoplastic treatments were received by 41% (86/209) of patients. Subsequent nivolumab was received by 87% of patients. 191 patients (91%) reported at least 1 grade (G) 1 to 2 adverse event (AE). The most common G1 to G2 AEs were fatigue (113 [60%]), mucositis (100 [52%]), hand-foot syndrome (HFS) (91 [47%]), diarrhoea (79 [41%]), hypertension (67 [35%]), and hypothyroidism (60 [31%]). 78 G3 AEs ere reported: the most common were fatigue (19 [24%]) and diarrhoea (18 [23%]). Permanent discontinuations from the study owing to AEs was observed in 7 patients: three for G3 diarrhea, one of which manifested also G3 renal injury, two for G3 asthenia, one for G3 HFS and one for G3 mucositis. At least 131 patients (63%) required a dose reduction and 86 (41%) required a transitory interruption to manage toxic effects. Conclusions: Our data confirmed that front-line Cabozantinib is effective and safe in an unselected real-life population of patients with intermediate-poor mRCC, including non-clear cell histologies.

Safety and Efficacy of Splenic Irradiation for Non-Hodgkin Lymphoma

Background: Splenic infiltration and associated splenomegaly is a challenging complication of non-Hodgkin lymphoma (NHL). The choice between splenectomy and splenic radiation (RT) is controversial, with little data to provide guidance in NHL. We aim to assess the tolerability and efficacy of splenic RT in NHL. Methods: We reviewed NHL patients treated from 2002 to 2021 with RT to the spleen alone. Splenomegaly was defined as vertical length >13cm. Splenic volume was obtained by manual contouring in MIM PACS 6.9.7 on the baseline pre-RT CT scan and the CT scan at best splenic response post-RT. PET response was evaluated by Lugano criteria. Adverse events (AEs) were retrospectively graded by clinicians using CTCAE v5.0. Cell counts were collected at baseline pre-RT and through 90 days post-RT completion; cell counts were censored at initiation of cytotoxic chemo post-RT if received. Significance was assessed with the Kruskal Wallis test. Results: 21 patients (11 diffuse large B-cell lymphoma (DLBCL), 5 marginal zone lymphoma (MZL), 4 mantle cell lymphoma (MCL), 1 follicular lymphoma) were identified with 23 courses of splenic RT. Median age was 75 (42-94); median KPS was 80 (50-90). Most patients (57%) had splenic only disease. Median splenic height pre-RT was 13.6 cm (6.4-26.6); 13 patients (57%) had baseline splenomegaly. Median splenic volume was 682cc (104-3355). 11 patients (48%) were symptomatic pre-RT (most frequently with pain: n=7, dyspnea: n=4, or nausea: n=4). 91% had any cytopenia before RT with median baseline absolute neutrophil count (ANC) 2.3 (0.2-10.6), hemoglobin 9.8 (7.1-13.8), and platelets 93 (9-221). RT was performed with definitive (n=11) or palliative (n=9) intent, or as bridging to chimeric antigen receptor T cells (n=3). Median dose was 30Gy for DLBCL (10.8-45), and 4Gy for MCL/MZL/FL (0.6-20); 10 patients received ≥20Gy. RT was well tolerated with 43% of courses without AEs and 57% with G1-2 AEs. AEs with frequency >10% were G1 fatigue (n=6), G1 anorexia (n=5), G1 nausea (n=5), G1 diarrhea (n=4), and G2 fatigue (n=4). There were no G3-4 AEs. One patient died from respiratory failure secondary to fungal pneumonia which was not felt to be attributable to splenic RT. Median nadirs in the 19 patients with cell count data: ANC 1.6 (0.2-3.8), hemoglobin 10.1 (6-13.4), platelets 70 (6-182) with 8, 6, and 15 median days from RT start to nadir (Table 1). ANC and platelets were disproportionately affected (median reduction: 26% and 28% for ANC and platelets, respectively vs. 5% for hemoglobin; p=0.006). There were no significant differences in reductions in ANC, platelets, or hemoglobin by RT dose (≥20Gy vs. <20Gy; p>0.1). In 3 patients (14%) cytopenias completely normalized post-RT. In most patients, cell counts normalized to pre-RT baseline (see Table 1). 4/13 symptomatic patients (31%) experienced complete relief. Median reduction in splenic volume was 34% (0-90%) with no significant difference in cytoreduction between low and high dose RT groups (median 27% reduction in <20Gy and 46% in ≥20Gy; p=0.2), see Figure 1. Overall response rate (ORR) by PET was 85% (35% complete response, 50% partial response, 10% stable disease, 5% progressive disease). With a median follow up of 12mo, median duration of radiographic response was 8mo (0.5-103) with more durable response at ≥20Gy (median 35 vs. 4mo, p=0.01). Conclusion: Splenic RT was well tolerated and had a high ORR of 85%. Radiographic response was more durable at doses ≥20Gy. Larger sample sizes with homogenous histology are needed to further evaluate the impact of dose on cell counts, clinical toxicity, and symptomatic relief. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A CRUK first-in-human phase I trial of LY3143921, a novel CDC7 inhibitor, in patients with advanced solid tumors.

3103 Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) &amp; diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue &amp; hyponatraemia and G2 diarrhea, anorexia &amp; lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax &amp; AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.

P-239 Management of gastric cancer in vulnerable patients: Is there a particularity?

Gastric cancer is the third leading cause of cancer death in the world and the fourth in Marrakech with an ASIR of 4.15 per 100.000 residents. It is frequently diagnosed in the elderly and is associated with rapid deterioration of general health. Management of this frail population has always been a challenge because being less included in trials. The aim of our study is to make a descriptive analysis regarding the management of frail patients. We conducted a descriptive retrospective study evaluating 62 vulnerable patients diagnosed with gastric cancer between 2020-2021 at the medical oncology department of the Mohammed VI University Hospital in Marrakech-Morocco. Vulnerable patients were defined by an age ≥ 70 years old and/or those with a performance status ≥ 2. Between 2020-2021, 150 patients were diagnosed with gastric cancer, only 62 patients were included in this study. Most of our patients were males (60% vs 40%). The average age at diagnosis was 64 years of which 35 patients (56.4%) were aged ≥ 70 years and 48 (77%) had a PS ≥ 2. 19 patients (30.6%) had comorbidities. For elderly patients: 31 (88.5%) had a G8 score ≤ 14. The most frequent histological type was adenocarcinoma 57 (92%), of which 12 (21%) were in the form of signet ring cell type. 30.6% of the patients had locally advanced tumor and 63% had metastatic tumor. 35 of patients (56.5%) received chemotherapy, of which 83% received bi-chemotherapy such as CAPOX or FOLFOX in 86% of the cases and 17% received CAPECITABINE as a monotherapy. 12% underwent surgery after neoadjuvant chemotherapy, 18 patients (29%) were declared palliative care due to deterioration of general condition (PS 3-4), and 8 patients (13%) were lost to follow-up. Among patients who received chemotherapy: 33.60% presented chemotherapy induced toxicities including peripheral neuropathy G1-G2 in 33% of cases, 24% with G1-G4 neutropenia, 24% with asthenia 14% with G1 diarrhea. Data of first PFS and Overall survival are not mature, further follow-up is needed to provides these results. In our study, age was not an indicator for not giving chemotherapy. However, the decision to administer chemotherapy depended on the performance status. Bi-chemotherapy was not associated with excessive toxicity.

Phase I/II trial of RVU120 (SEL120), a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors.

e15091 Background: CDK 8 /CDK19 are kinases involved in transcriptional control of embryonic development and cellular homeostasis via the mediator complex. They are also described to maintain tumor dedifferentiation and stem cell properties. A variety of cancer cells hijack the mediator complex and targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: A Phase I/II clinical trial of RVU120 in solid tumors is currently ongoing (NCT05052255). Patients with metastatic or advanced solid tumors without available treatments receive increasing doses of RVU120 as a single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle. Primary objectives of the study are safety / tolerability of RVU120 as single agent and determination of the recommended Phase II dose (RP2D) via a 3+3 dose escalation design. Secondary objectives include objective response rate (ORR) (RECIST criteria v1.1) and PK of RVU120. Results: As of 11FEB 2022, 5 pts have been enrolled into the trial: 3 into cohort 1, 75 mg dose, 2 into cohort 2, 100 mg. None of the pts experienced a DLT, SAEs or &gt; Grade 3 AE. Treatment-related AEs were all G1 except for G2 diarrhea and weakness. Cohort 1 patients had at least 1 post-baseline tumor assessment. A 62 YO patient, stage IV esophago-gastric junction carcinoma, metastases to the liver, retroperitoneum, adrenal gland and portocaval lymph nodes, progressing after 4 lines of previous therapy, achieved a SD with a +4% change of target lesion size and progressed in cycle 6. A 65 YO patient, stage IV adenoid cystic carcinoma of the trachea, metastases to the lung and refractory to antiandrogens and radiotherapy, achieved a SD with -4% change of target lesion size after 3 cycles and is currently ongoing in cycle 5. A 43 YO pt stage IV thymic carcinoma, metastases to the lung, mediastinum, pleura and lymph nodes, progressing under cisplatin/etoposide, stopped study drug at the end of cycle 3 for PD in non-target lesions, target lesions increased by 11%. Cohort 2 patients, a 65 YO pt with pancreatic cancer stage IV, metastases to liver and lung, and a 55 YO pt with TNBC stage IV, metastases to the lung, will be evaluated end of cycle 3. Conclusions: In the first dose escalation level with single agent RVU120, no DLTs or ≥G3 AEs were observed in patients with previously progressive solid tumors. Initial assessments in 3 pts demonstrated stable disease in 2 patients. Collection of further data at higher doses is ongoing with 2 patients enrolled at 100 mg. Clinical trial information: NCT05052255.

Long-term safety of inavolisib (GDC-0077) in an ongoing phase 1/1b study evaluating monotherapy and in combination (combo) with palbociclib and/or endocrine therapy in patients (pts) with PIK3CA-mutated, hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (BC).

1052 Background: Dysregulating mutations in PIK3CA, encoding the PI3K p110α subunit, occur in ̃40% of HR+/HER2– BCs. Inavolisib is a PI3Kα-specific inhibitor that also promotes degradation of mutant p110α. It has demonstrated encouraging preliminary antitumor activity in pts with PIK3CA-mutated HR+ BC as a monotherapy, and in combo with other anticancer agents. Methods: We included pts from NCT03006172 on treatment ≥1 year with inavolisib alone (Arm A), or in combo with palbo + letrozole (letro) (B), letro (C), fulvestrant (fulv) (D), or palbo + fulv (E; + metformin in Arm F for pts with body mass index ≥30 and/or HbA1c ≥5.7%). Inavolisib was administered orally daily (PO QD) at 3, 6, 9, or 12 mg (3+3 dose-escalation design); letro at 2.5 mg PO QD; palbo at 125 mg PO QD for 21/28 days; and fulv at 500 mg intramuscularly every 4 weeks, in 28-day cycles until intolerable toxicity/disease progression. Safety was assessed by NCI-CTCAE v4. Results: 57 female pts were included (cutoff 07/26/21; N = 1, 18, 6, 12, 15, 5 in Arms A–F); median age: 57 years (range 33–80); median lines of prior therapy: 2 (1–7). All but 2 pts, both in Arm B (3 mg), were assigned the 9 mg inavolisib recommended phase 3 dose. Overall median treatment duration: 19 months (range 12–45); median inavolisib cumulative dose intensity, 95%. The most frequent treatment-related adverse events (AEs; in ≥20 pts/35%) were hyperglycemia (68%), stomatitis (68%; grouped terms), neutropenia (58%), diarrhea (51%), nausea (39%), alopecia (35%), and rash (35%; grouped terms). The most frequent treatment-related Grade (G) 3–4 AEs (≥2 pts/4%) were neutropenia (47%), hyperglycemia (16%), leukopenia (9%), thrombocytopenia (9%), lymphopenia (7%), weight decreased, and hypokalemia (4% each). G3–4 neutropenia, leukopenia, thrombocytopenia, and lymphopenia were all reported in palbo arms. One G5 AE of pleural effusion was reported (disease progression-related). 39 pts (68%) had ≥1 AE resulting in study treatment modification (drug interruption/dose reduction/treatment withdrawal); 11 (19%) had an inavolisib dose reduction and 2 (4%) discontinued treatment due to an AE (1 related G2 diarrhea, 1 unrelated G3 cerebrovascular disorder). AEs typically occurred during the first 6 months and tended to be less frequent in later cycles. No new safety signals were observed with long-term inavolisib use. Conclusions: These data indicate acceptable long-term tolerability. The safety profile of pts on study treatment with inavolisib alone or in combo with endocrine-based anticancer therapies for ≥1 year was similar to that reported for the overall study population. Updated data will be presented. A phase 3 study of inavolisib + palbo + fulv is enrolling (NCT04191499; INAVO120). Clinical trial information: NCT03006172.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases

IntroductionTrametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Methods and MaterialsPatients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1–3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. Results10 patients were enrolled (median age-59 [47–64], BM-5 [1–10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3–4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. ConclusionsIn a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): Preliminary data of phase I study.

490 Background: Niraparib (N) is a (PARP)-1/-2 inhibitor and Cabozantinib (C) is a tyrosine kinase (TK) inhibitor that targets VEGF signalling via inhibition of multiple TK receptors including c-MET and TAM kinases (TYRO3, AXL, MER). The c-Met receptor TK is abnormally activated and could be decrease response to PARP inhibitors. Preclinical data reveals that treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. A phase (Ph) I-II study was designed to explore the safety and efficacy of the combination of N + C in genitourinary cancers. Methods: Multicenter, open-label Ph I-II study (NCT03425201). Confirmed histopathological diagnosis of either metastatic urothelial carcinoma (mUC) or advanced clear cell renal cell carcinoma previously treated with a maximum of two previous regimens. Adequate bone marrow, liver and renal functions were required. The Ph I portion aimed to identify the maximum tolerated dose (MTD) and recommended ph II dose (RP2D). Pt received N and C p.o. once daily in 28-day cycles: Dose level 1 (DL1) N/C 100/20 mg; DL2 200/20 mg; DL3 200/40 mg; DL4 200/60 mg. A further amendment developed DL1.1 100/40 mg. Pt were accrued to each dose level in cohorts of 6 pt until the MTD was achieved (defined as highest dose at which ≤1 out of 6 pt experience a DLT, evaluated during the first 2 cycles). Results: Nineteen evaluable pt for DLT were included, 14 of them had UC. There was no DLT at DL1. Two out of the first 6 evaluable pt in DL2 had DLT (G3 thrombopenia and anemia and G3 diarrhea respectively). Upon analysis of these pt it was agreed to include 3 additional new pt for evaluation. Two pt were included with one presenting a DLT (G3 hepatic toxicity). Enrolment then continued in a new DL 1.1 cohort and 1 of 6 pts had DLT (G3 mucositis), being then considered the RP2D. No toxic deaths were reported. Six pt (32%) received at least 10 cycles and 9 pt (47%) received at least 6 cycles. Three patients (16%) achieved partial response (all of them with mUC disease) and 14 (74%) stable disease. Conclusions: N plus C combination can be safely administered with a manageable toxicity profile and preliminary efficacy was reported in mUC heavily pretreated pts. The RP2D is N 100 mg plus C 40 mg qd. Ph II study is now recruiting mUC patients. Clinical trial information: NCT03425201. [Table: see text]