MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Johann S. De Bono ◽  
Mark T. Fleming ◽  
Judy Sing-Zan Wang ◽  
Richard Cathomas ◽  
Marna Williams ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Antibody Drug Conjugate ◽  
Starting Dose ◽  
Duration Of Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Composite Response

99 Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to < 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.

A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4000-4000 ◽  
Author(s):  
Salvatore Siena ◽  
Maria Di Bartolomeo ◽  
Kanwal Pratap Singh Raghav ◽  
Toshiki Masuishi ◽  
Fotios Loupakis ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Drug Discontinuation ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Grade 5 ◽  
Duration Of Response ◽  
Grade 3

4000 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. DESTINY-CRC01 (DS8201-A-J203; NCT03384940) is a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC. Methods: Pts with centrally confirmed HER2-expressing, RAS–wild type mCRC that progressed on ≥ 2 prior regimens received T-DXd 6.4 mg/kg every 3 weeks (q3w) in 3 cohorts (A: HER2 IHC 3+ or IHC 2+/ISH+; B: IHC 2+/ISH−; C: IHC 1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A; secondary endpoints included, disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and ORR in cohorts B and C. Results: At data cutoff (Aug 9, 2019), 78 pts (A, 53; B, 7; C, 18) had received T-DXd. Median age was 58.5 y (range, 27-79 y), 52.6% of pts were male, and 89.7% had left colon or rectum cancer; median number of prior regimens was 4 (range, 2-11); all pts had prior irinotecan. Median treatment duration was 3.5 mo (95% CI, 2.1-4.3 mo; cohort A, 4.8 mo [95% CI, 3.9-5.8 mo]); 38.5% of pts remained on T-DXd treatment. The confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6%-59.6%) in cohort A, including 1 CR and 23 PRs; median DOR was not reached (95% CI, 4.2 mo-NE). The ORR in pts with prior anti-HER2 treatment was 43.8% (7/16 pts; 95% CI, 19.8%-70.1%). The DCR was 83.0% (44/53 pts; 95% CI, 70.2%-91.9%); median PFS was 6.9 mo (95% CI, 4.1 mo-NE); median OS was not reached. No responses were observed in cohorts B or C. Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 61.5% of pts (48/78); the most common (≥10%) were decreased neutrophil count (21.8%) and anemia (14.1%). Seven pts (9.0%) had TEAEs leading to drug discontinuation. Five pts (6.4%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (2 grade 2; 1 grade 3; 2 grade 5 [the only drug-related deaths]). Conclusions: Overall, T-DXd 6.4 mg/kg q3w demonstrated remarkable activity in pts with HER2-expressing mCRC refractory to standard therapies, with a safety profile consistent with previous results. ILD is an important risk and requires careful recognition and intervention. Clinical trial information: NCT03384940 .

Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1077-1077
Author(s):  
Joyce O'Shaughnessy ◽  
Kevin Punie ◽  
Mafalda Oliveira ◽  
Filipa Lynce ◽  
Sara M. Tolaney ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Antibody Drug Conjugate ◽  
Phase 3 ◽  
Chemotherapy Agent ◽  
Recist 1.1 ◽  
Duration Of Response ◽  
Grade 3

1077 Background: In pts with pretreated mTNBC, standard-of-care chemotherapy is associated with low objective response rates (ORRs) and short median progression-free survival (PFS). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated FDA approval for treatment of pts with mTNBC who have received ≥2 prior therapies for metastatic disease. The confirmatory phase 3 ASCENT study (NCT02574455) in pts with relapsed/refractory mTNBC demonstrated a significant survival benefit of SG over TPC (median PFS: 5.6 vs 1.7 mo, HR 0.41, P< 0.0001; median overall survival [OS]: 12.1 vs 6.7 mo, HR 0.48, P< 0.0001) with a tolerable safety profile. Here we summarize efficacy results for SG vs each TPC agent in ASCENT to examine how each TPC agent performed individually. Methods: Pts had mTNBC refractory to or progressing after ≥2 prior standard chemotherapy regimens. Pts were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8, every 21 days) or single-agent TPC (eribulin, vinorelbine, capecitabine, or gemcitabine). Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Secondary endpoints were ORR per RECIST 1.1, duration of response, OS, and safety. Outcomes for each of the agents in the TPC arm were analyzed and compared with SG. Results: Of 529 pts enrolled, 468 were BMNeg. Among pts in the TPC cohort (n = 233), eribulin was the most commonly chosen chemotherapy (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29). Treatment with eribulin, vinorelbine, capecitabine, and gemcitabine resulted in shorter median PFS vs SG (2.1, 1.6, 1.6, and 2.7 vs 5.6 mo, respectively); similar results were observed for median OS (6.9, 5.9, 5.2, and 8.4 vs 12.1 mo), ORR (5%, 4%, 6%, and 3% vs 35%), and clinical benefit rate (CBR; 8%, 6%, 10%, and 14% vs 45%). Key grade ≥3 treatment-related adverse events (TRAEs) with TPC overall vs SG included neutropenia (33% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), and anemia (5% vs 8%). Key grade ≥3 TRAEs with eribulin vs SG included neutropenia (30% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), anemia (2% vs 8%), and peripheral neuropathy (2% vs none), respectively. The safety profiles of vinorelbine, capecitabine, and gemcitabine combined were consistent with that of TPC overall and with eribulin. One treatment-related death was reported for the TPC arm (eribulin) and none with SG. Conclusions: The efficacy benefit observed with SG vs TPC in pts with mTNBC was retained when evaluating each TPC chemotherapy agent individually. These results confirm that SG should be considered as a new standard of care in pts with pretreated mTNBC. Clinical trial information: NCT02574455 .

scholarly journals Real-world experience with Temozolomide & Sativex in patients with recurrent High Grade Gliomas

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv13-iv14
Author(s):  
Lillie Shahabi ◽  
Kerlann Le Calvez ◽  
Seema Dadhania ◽  
Catherine Blake ◽  
James Wang ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Progressive Disease ◽  
Phase 1 ◽  
Median Number ◽  
Phase 1 Study ◽  
Malignant Brain Tumour ◽  
Mri Scans ◽  
Recent Phase ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background Glioblastoma (GBM) is the most common malignant brain tumour in adults with a median survival from progression of 8 months. A recent phase 1 study of temozolomide (TMZ) and 1:1 CBD:THC (Sativex) offers evidence of efficacy in patients with recurrent GBM (NCT01812603). Methods All patients receiving TMZ & Sativex (75mg/m2 daily d1 – 21 q28; Sativex continuously) for relapsed GBM or grade 3 astrocytoma at our centre were identified. Patient, tumor and treatment characteristics were recorded, and response based on sequential MRI scans using modified RANO criteria assessed. Results 13 patients were treated over 18 months. The median age was 56; 69% were male. All had received initial chemo-radiotherapy (12 patients: 60 or 59.4Gy/30–33#; 1 patient: 45Gy/15#). 6 patients underwent reresection at recurrence. 4 patients were treated at first progression, 7 at second progression, and 2 at third or later progression. The median number of cycles of TMZ and sativex was 2. The combination treatment was tolerated well by all patients treated, with no Grade 3 or 4 toxicities, the only complaints being of discomfort in mouth after spray and ‘spaced out feeling’. Patients stopped treatment due to evidence of progressive disease on sequential MRI sign or physical deterioration. Median Overall Survival (OS) from initiation was 5.9 months (177 days); Progression Free Surival (PFS) at 3 months was 50%. Conclusion These results highlight some discrepancies in OS in comparison to the previous trial (NCT01812603), but our patients were treated at second/ third recurrence. We agree that the combination is well tolerated.

Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4525-4525 ◽  
Author(s):  
Noah M. Hahn ◽  
Thomas Powles ◽  
Christophe Massard ◽  
Hendrik-Tobias Arkenau ◽  
Terence W. Friedlander ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Kidney Injury ◽  
Progression Free Survival ◽  
Anticancer Therapy ◽  
Clinical Activity ◽  
Open Label ◽  
Duration Of Response ◽  
Grade 3

4525 Background: Anti-PD-L1 immunotherapy shows promising clinical activity in UC. We report a planned update of the safety and efficacy of durvalumab in patients (pts) with locally advanced/metastatic UC from a multicenter, phase 1/2 open-label study. Methods: Pts received durvalumab 10 mg/kg every 2 weeks (Q2W) up to 12 months (mo) or until unacceptable toxicity, progression, or starting another anticancer therapy. Primary endpoints were safety and confirmed objective response rate (ORR) by blinded independent central review (RECIST v1.1). Duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Tumor PD-L1 expression was assessed by Ventana SP263 assay (PD-L1 high = ≥25% PD-L1 expression on tumor or immune cells). Results: As of Oct 24, 2016 (data cutoff [DCO]), 191 pts had received treatment. Median follow-up was 5.78 mo (range, 0.4–25.9). All pts had Stage 4 disease and 99.5% had prior anticancer therapy (95.3% post-platinum). As of DCO, ORR was 17.8% (34/191), including 7 CRs, with responses observed regardless of PD-L1 status (Table). Responses occurred early (median time to response, 1.41 mo) and were durable (median DoR not reached [NR]). Median PFS and OS were 1.5 mo (95% CI, 1.4, 1.9) and 18.2 mo (95% CI, 8.1, not estimable [NE]), respectively; the 1-year OS rate was 55.0% (95% CI, 43.9%, 64.7%). Grade 3/4 treatment-related AEs occurred in 6.8% of pts; grade 3/4 immune-mediated (im)AEs occurred in 4 pts; 2 pts discontinued due to imAEs (acute kidney injury and autoimmune hepatitis). Conclusions: Durvalumab 10 mg/kg Q2W shows favorable clinical activity and an excellent safety profile in locally advanced/metastatic UC pts. Table. Antitumor activity in UC pts, including second-line or greater (≥2L) post-platinum pts Clinical trial information: NCT01693562. [Table: see text]

Phase 1 study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5038-5038 ◽  
Author(s):  
Michael J. Morris ◽  
Nicholas J. Vogelzang ◽  
Oliver Sartor ◽  
Alison Armour ◽  
Michael Groaning ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Median Number ◽  
Selection Strategy ◽  
Microtubule Inhibitor ◽  
Normal Tissues ◽  
Castrate Resistant ◽  
Number Of Cycles ◽  
Spect Scan

5038 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, but not in most normal tissues, making it a potential therapeutic target. We are conducting a two-part phase 1 dose escalation/expansion study of EC1169, a PSMA-targeted conjugate of the microtubule inhibitor tubulysin B hydrazide in mCRPC. The utility of the PSMA-targeted companion imaging agent 99mTc-EC0652 is also being evaluated as a patient selection tool. The safety, efficacy, and imaging-based PSMA selection strategy are being investigated in Part A (dose escalation) and Part B (2-stage, 2-cohort expansion). Methods: Part A pts were eligible if they progressed on abiraterone or enzalutamide, and were treated with a taxane. EC1169 was administered as an IV bolus on days 1, 8 every 21 days. Part B pts are enrolled in 1 of 2 cohorts, mCRPC taxane naïve (cohort 1, 45 pts) and taxane exposed (cohort 2, 40 pts). Prior to treatment, pts undergo a 99mTc-EC0652 SPECT scan. The primary endpoint of Part B is median radiographic progression-free survival (rPFS). Other study evaluations are OS, PSA, and CTC-based biomarkers. Results: Part A is now complete: the RP2 dose is 6.5 mg/m2, on the basis of non-DLT transaminitis. 20 Part A/B pts have been treated at the RP2 dose (7 taxane naïve, 13 taxane exposed). Median age is 69 (range: 59-82). Median number of cycles is 2 (range: 1-7). 10 pts (50%) reported at least 1 treatment related AE. Most treatment related AEs are Gr1 and 2; G3 thrombocytopenia, fatigue, and constipation have occurred in 1 pt each. No Grade 4 treatment related AEs have been reported. No DLT or toxicity requiring dose reductions occurred. Four taxane-exposed pts in Part B have reached their first 9 wk radiographic assessment, of which two have soft tissue disease. One of those two patients (50%) has achieved an unconfirmed RECIST PR. Conclusions: The RP2 dose of EC1169 is 6.5 mg/m2. EC1169 has been well tolerated in 20 pts at the RP2 dose. Imaging with 99mTc-EC0652 suggests excellent disease localization supporting a PSMA-targeted therapeutic strategy. There is evidence of anti-tumor activity in both the dose escalation and expansion cohorts. Clinical trial information: NCT02202447.

Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for muscle invasive urothelial bladder cancer (MIUBC): Preliminary results of the GETUG/AFU V05 VESPER trial on toxicity and pathological responses.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 437-437 ◽  
Author(s):  
Stephane Culine ◽  
Gwenaelle Gravis ◽  
Aude Flechon ◽  
Michel Soulie ◽  
Laurent Guy ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Median Number ◽  
Phase Iii ◽  
Perioperative Chemotherapy ◽  
Urothelial Bladder ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Muscle Invasive ◽  
Dose Dense ◽  
Number Of Cycles

437 Background: The optimal perioperative chemotherapy regimen for patients (pts) with MIUBC is not defined. Methods: Between February 2013 and February 2018, 494 pts were randomized in 28 French centres and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). The primary endpoint was the progression-free survival at 3 years. Secondary endpoints included toxicity, pathological responses and overall survival. Results: In the neoadjuvant group, 218 pts received dd-MVAC and 219 pts GC. The median number of cycles was 6 (0-6) and 4 (1-4), respectively. 60% of pts received 6 cycles in the dd-MVAC arm, 84% received 4 cycles in the GC arm. 199 pts (91%) and 198 (90%) pts underwent surgery, respectively. Complete pathologic responses (ypT0pN0) were observed in 84 (42%) and 71 (36%) pts, respectively (p=0.02). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) pts, respectively (p=0.002). In the adjuvant group (57 pts), the median number of cycles was 5 (1-6) and 4 (1-4), respectively. 40% of pts received 6 cycles in the dd-MVAC arm, 60% received 4 cycles in the GC arm. Most of CTCAE grade ≥ 3 toxicities concerned hematological toxicities. At least one of these where reported for 125 (50%) pts in the dd-MVAC group and 134 (54%) pts in the GC group (p=NS). Gastrointestinal (GI) grade ≥ 3 disorders were more frequently observed in the dd-MVAC arm (p<0.0001) as well as grade ≥ 3 asthenia (p<0.00001). Four deaths (3 in the dd-MVAC) occurred during chemotherapy. Conclusions: Complete pathological responses and organ-confined status were more frequently observed in the dd-MVAC arm. Toxicity was manageable with more severe asthenia and GI side effects in the dd-MVAC arm. Clinical trial information: 2012-000563-25.

scholarly journals Everolimus in Combination with Rituximab Induces Complete Responses in Heavily Pretreated Diffuse Large B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1635-1635 ◽  
Author(s):  
Jeffrey A. Barnes ◽  
Eric Jacobsen ◽  
Yang Feng ◽  
Arnold S. Freedman ◽  
Ephraim P. Hochberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Progression ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3 ◽  
Kinase Expression

Abstract Abstract 1635 Background: Patients with diffuse large B cell lymphoma (DLBCL) who are primarily refractory to, or relapse after initial therapy with R-CHOP have a poor outcome and novel therapies are needed in these clinical scenarios. Pre-clinical data suggests that inhibition of mammalian target of rapamycin (mTOR) induces cell cycle arrest in DLBCL cell lines. We sought to investigate the activity of everolimus, a potent inhibitor of mTOR, combined with rituximab in this population Methods: We conducted a phase II study employing a Simon's optimal two-stage design. Eligible subjects had previously received ≥1 prior line of chemotherapy and had either relapsed after autologous stem cell transplantation or were not candidates for transplant. Everolimus was administered orally once daily at 10 mg on days 1–28 of a 28-day cycle. Rituximab 375mg/m2 was administered IV weekly during the first cycle, then on Day 1 of cycles 2–6. Subjects received up to 6 cycles of treatment in the absence of disease progression. Patients without disease progression after 6 cycles continued everolimus monotherapy for up to 6 additional cycles in the absence of disease progression. The primary end point was overall response rate (ORR) as defined by the Revised International Workshop Response Criteria (2007). Secondary endpoints included progression free survival (PFS) at 1 year, duration of response, toxicity, and correlation of response with baseline tissue AKT, pAKT, and p70s6 kinase expression and p70s6 kinase expression from PBMC during treatment. The study was designed with 90% power to show a 30% ORR, with a 10% ORR considered unworthy for further study. Results: Between July 2009 and June 2010, 25 eligible subjects were enrolled. The median age was 65 (range 33–87). The median number of prior therapies was 4 (range 1–7), median time from prior therapy was 31 months (range 4–261), and 5 (20%) of subjects had undergone prior autologous stem cell transplant. Nineteen (76%) patients presented with advanced stage at relapse, 16 (64%) had an elevated LDH and 10 (40%) had greater than 1 extranodal site at relapse. The median number of cycles completed was 2 (range 0–8) and 5 (20%) subjects received more than 6 cycles. The ORR was 24% (90% CI [11%-42%] with 2 subjects having a CR and 4 with a PR. The median duration of response was 11 months. One subject with a CR remained on therapy a total of 12 cycles and is alive and free of disease 8 months post treatment. A second subject with a relapse after allogeneic transplant obtained CR to everolimus and remains in remission after donor lymphocyte infusion. A third subject with a PR completed 6 cycles followed by a full intensity unrelated allogeneic transplant and is alive and well at 19 months post transplant. At a median follow of 4.4 months (range 1.8–15), 29% of patients remained progression-free (95%CI [11%,47%]). The median progression-free survival was 2.6 months (95% CI [1.7, 3.8]). Fourteen patients remain alive. Treatment was well tolerated with 10 episodes of grade 3/4 neutropenia but only 1 episodes of febrile neutropenia. There were 3 episodes of grade 3 hypertriglyceridemia and no episodes of hyperglycemia. Correlative studies including pharmacodynamic evidence of mTOR inhibition and baseline activation of the mTOR pathway are ongoing. Conclusions: These data indicate that the combination of everolimus with rituximab is well tolerated and able to induce responses in a proportion of subjects with relapsed DLBCL, some of which are sustained and may serve as a bridge to allogeneic stem cell transplantation. Ongoing correlative studies are assessing predictive biomarkers of response. Disclosures: Off Label Use: Everolimus is not FDA-approved for treatment of DLBCL. Hochberg:Genentech: Consultancy. Fisher:Genentech: Consultancy. Abramson:Novartis: Consultancy; Genentech: Consultancy.

Phase II study of bevacizumab in combination with cisplatin and docetaxel as first-line treatment of patients (p) with metastatic non-squamous non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19023-e19023
Author(s):  
N. Ferrer ◽  
M. Cobo ◽  
A. Paredes ◽  
M. Méndez ◽  
J. Muñoz-Langa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Median Number ◽  
Line Treatment ◽  
Eligibility Criteria ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Grade 3 ◽  
Number Of Cycles

e19023 Background: Bevacizumab (B), in addition to platinum-based chemotherapy, is indicated for 1st-line treatment of p with advanced NSCLC other than predominantly squamous cell histology. B has been shown to improve progression free survival (PFS) and overall survival (OS) when combined with cisplatin/gemcitabine and carboplatin/paclitaxel, respectively. However, there are limited data on the safety and efficacy of B in combination with other widely used chemotherapy doublets for NSCLC. This is a single-arm, open- labeled, single-stage phase II trial of cisplatin (C), docetaxel (D) and B for NSCLC. Methods: Eligibility criteria: chemo- naïve, stage IIIB wet or IV, non-squamous NSCLC, PS 0–1, no brain metastases and no history of gross hemoptysis. P received D (75 mg/m2), C (75 mg/m2), and B (15 mg/kg iv) on day 1 every 3 weeks for up to 6 cycles, followed by B 15 mg/kg alone every 3 weeks until disease progression or toxicity. Primary endpoint: PFS. Results: 50 p were enrolled (enrollment completed): 24% female, median age 60 (36–74), PS 1: 64%, adenocarcinoma: 72%; stage IV: 92%. Two p did not start treatment. Median follow-up is 5.3 months (range 0–13.6). Median number of cycles of B was 7 (range 0–18). 56% completed 6 cycles of treatment; 24% received ≥ 12 cycles of B. Most frequent grade ≥ 3 toxicities: diarrhea (14.6%), fatigue (14.6%), dyspnea (9.8%), anorexia (4.9%), alopecia (4.9%), esophagitis (4.9%), constipation (4.9%), mucositis (12.2%), proteinuria (4.9%); hematological toxicities: neutropenia (22%), febrile neutropenia (9.8%), leucopenia (14.6%), lymphopenia (4.9%). Of interest, 41.5% developed grade <3 epistaxis and 17% hypertension (1 p grade 3). One p died due to hemoptysis. 46 p were evaluable for response: 29 PRs (ORR: 63%). 18 of 48 p have experienced progression or death with a median SLP of 7.8 months (95% CI: 6.6-NR). Median OS is 13.5 months (95% CI: 12.7–13.6; 81.2% p censored); 1-year survival is 83.9% (95% CI: 67.4%-92.5%). Conclusions: Treatment with C, D and B, followed by maintenance B in 1st line of advanced non-squamous NSCLC shows an acceptable toxicity profile and promising efficacy. Final results will be presented. [Table: see text]

Cisplatin and capecitabine with and without docetaxel as a first-line chemotherapy in patients with metastatic gastric carcinoma: Single clinical experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15194-e15194
Author(s):  
Mekhty Narimanov ◽  
Alexey Tryakin ◽  
Varlam Zarkua ◽  
Igor Bazin ◽  
August Garin ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Median Overall Survival ◽  
Progression Free Survival ◽  
Primary Prophylaxis ◽  
Median Number ◽  
First Line ◽  
Free Survival ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Line Chemotherapy

e15194 Background: Cisplatin and capecitabine and docetaxel are active agents for treatment of metastatic gastric carcinoma. We underwent analysis of efficacy and toxicity of douplet (CX ) and triplet (DCX) regimens which were used in our department as a first-line chemotherapy in patients with metastatic gastric carcinoma. Methods: Pts with metastatic gastric carcinoma were nonrandomly allocated to DCX regimen (docetaxel 75 mg/m2 i.v. day 1, cisplatin 75 mg/m2 i.v. day 1, capecitabine 1650 mg/m2 per os days 1-14) or CX regimen (cisplatin 75 mg/m2 i.v. day 1, capecitabine 2000 mg/m2 per os days 1-14 ). Up to 6 cycles were provided every 3 weeks. G-CSF was not routinely used for primary prophylaxis. Results: From 2008 to 2012 81 pts were included in the study (DCX – 37 pts, CX – 44 pts). Pts characteristics were similar in both groups (table 1). Median number of cycles in both groups was 5 (range, 1-6). Grade 3-4 toxicity (per cycle) in DCX and CX groups were neutropenia 24,9% and 16,1%, deep venous thrombosis – 2% and 0%, diarrhea – 6.2% and 7,4%, stomatitis – 3.8% and 2,2%, infection – 11% and 0%, anemia 14% and 13,5% pts, respectively. No toxic deaths were observed. Median progression-free survival (PFS) in DCX and CX were 7,5 months (95% CI 6,1-8,9) and 5,4 months (95% CI 5,0-6,2; p=0.0009), median overall survival (OS) 14,5 months (95% CI 10,1-18,9) and 9,3 months (95% CI 9,2-10,2; p=0.0018), respectively. Conclusions: Addition of docetaxel to the combination of cisplatin and capecitabine associates with significant improvement of PFS and OS. Higher rate of infection requires use of G-CSF in primary prophylaxis. [Table: see text]

A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3032-3032
Author(s):  
Antonio Jimeno ◽  
Mateusz Opyrchal ◽  
Jennifer Robinson Diamond ◽  
Christos Fountzilas ◽  
Bradley Corr ◽  
...  
Keyword(s):  
Oral Administration ◽  
Dose Level ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Pharmacologically Active

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

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