A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2570-2570 ◽  
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Ben Markman ◽  
Rachael Chang Lee ◽  
Michael Michael ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Combination Treatment ◽  
Single Agent ◽  
Low Frequency ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Wide Range ◽  
Grade 3 ◽  
Upper Gastrointestinal

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.[Table: see text]

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Howard L. Parnes ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
John Joseph Wright ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Objective ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Visceral Metastases ◽  
Carcinoma Of The Bladder ◽  
Grade 3

307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after >12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.

Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: Phase II study CA180088

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1011-1011 ◽  
Author(s):  
E. Mayer ◽  
J. Baurain ◽  
J. Sparano ◽  
L. Strauss ◽  
M. Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Single Agent ◽  
Dose Intensity ◽  
Similar Efficacy ◽  
Breast Cancers ◽  
Once Daily ◽  
Prior Therapy ◽  
Her 2 ◽  
Grade 3

1011 Background: SRC family kinases (SFKs) are involved in numerous signaling pathways including from ER and HER-2 receptors, as well as osteoclast function. Dasatinib is a potent oral inhibitor of SFKs. A phase II trial was performed in patients (pts) with ER+ and/or PR+ and/or HER-2-amplified progressive advanced breast cancer. Subsequent to study initiation, dasatinib demonstrated similar efficacy with a lower incidence of key side-effects at 100 mg once daily in CML and prostate cancer. Methods: Pts with measurable disease and progression after chemotherapy and other targeted agents were treated with dasatinib on a continuous twice-daily (BID) schedule; RECIST-defined response rate was primary endpoint. Results: Sixty-eight pts, 24 with HER-2-amplified and 44 with HER-2-normal, ER+ and/or PR+ disease, were treated. Original starting dose of 100 mg BID (23 pts) was reduced to 70 mg BID (45 pts) due to fluid retention, fatigue, or GI toxicity. Median age was 55 years; nearly all pts (93%) had prior therapy in advanced setting. 59 were radiographically-evaluable (8 discontinued for toxicity and 1 inevaluable). We observed 3 partial responses lasting 9, 9 and 8+ mos plus 6 stable disease ≥16 weeks (range 24–33 wks). All 9 controlled tumors were ER/PR+, 2 were also HER-2-amplified; thus, disease control rate was 19% in the 47 radiographically-evaluable pts with ER/PR+ disease. Median dose intensity was 136 mg/day at 70 mg BID and 175 mg/day at 100 mg BID; median duration of therapy was 1.8 mos in both dose groups. Most pts (75%) discontinued for disease progression. The most common drug-related AEs were diarrhea (49%), headache (34%), nausea (34%), asthenia (32%), pleural effusion (31%), musculoskeletal pain (25%), and vomiting (24%). Drug-related grade 3–4 AEs were reported in 37% of pts and comparable between doses, but related serious AEs were less frequent at 70 mg BID than 100 mg BID (16% vs 26%). Grade 3–4 laboratory abnormalities were uncommon. PK and biomarker analyses will be presented. Conclusions: Encouraging single-agent activity was observed with dasatinib in pts with advanced ER+ breast cancers. Future studies will address the combination of dasatinib with hormonal therapies using a better-tolerated once daily schedule. [Table: see text]

Phase II Study of Lenalidomide (CC-5013, Revlimid®) for Patients (pts) with Myelofibrosis (MF).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 377-377
Author(s):  
Jorge Cortes ◽  
Deborah Thomas ◽  
Srdan Verstovsek ◽  
Francis Giles ◽  
Miloslav Beran ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Myeloproliferative Disorders ◽  
Clinical Activity ◽  
Toxicity Profile ◽  
Prolonged Administration ◽  
Prior Therapy ◽  
Days Of Therapy ◽  
Grade 3 ◽  
Baseline Hemoglobin

Abstract Introduction: Thalidomide has been shown to induce responses in pts with MF but prolonged administration in these pts may be associated with neurotoxicity and other adverse events. Lenalidomide is the lead clinical compound in a new group of drugs called IMiDs®, which have immunomodulatory properties. It affects cytokine expression 200–5000 times more potently than thalidomide but lacks the teratogenecity, sedation and neurotoxicity. Methods: We thus designed a phase II study for pts with myelofibrosis (primary or associated with myeloproliferative disorders) with a platelet (plt) count of at least 30 x109/L. Pts may have received prior therapies, but were excluded if they had known hypersensitivity to thalidomide. Pts received lenalidomide 10 mg/day orally (5 mg daily for patients with platelet count less than 100,000 at study entry). Results: We have treated 41 pts. Their median age was 65 (range, 42 to 83). Thirty-six pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 12 (29%), interferon 11 (27%) (pegylated 7), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was <10g/dl in 19 (46%) (13, 32% transfusion dependent); platelets <100 x109/L in 12 (29%); neutrophils <1.5 x109/L in 2 (5%), and 20/34 (59%) had splenomegaly (median 10cm BCM, range 1 to 30) (7 prior splenectomy). Twenty pts are evaluable for response and toxicity (i.e., received at least 30 days of therapy, unless discontinued because of progression or toxicity). One pt discontinued therapy because of toxicity (grade 3 rash). Responses have been observed in 10 (50%) pts. These include CR in 2 pts (normalization of Hgb and WBC, respectively), PR in 2 pts (improvement in plts and hgb, ± spleen), hematologic improvement in 6 pts (improvement in plts 3, spleen 2, WBC 1). Three of 13 transfusion-dependent pts have become transfusion independent. The median time to response was 9 weeks (range, 2 to 22). Responses have been sustained for a median of 14 weeks (range, 2 to 28 weeks). Therapy has been well tolerated. The more common toxicities were rash in 12 (29%), and pruritus in 8 (20%). Grade ≥ 3 toxicities were thrombocytopenia (n=2), rash (n=1), fatigue (n=1), and neutropenia (n=1). Four (10%) pts have required dose reduction and 1 discontinued therapy because of toxicity (rash). Conclusion: We conclude that lenalidomide has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are justified.

Phase II Trial of Combination of Bortezomib and Rituximab in Relapsed and/or Refractory Waldenstrom Macroglobulinemia: Preliminary Results.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4494-4494
Author(s):  
Irene M. Ghobrial ◽  
Swaminathan Padmanabhan ◽  
Ashraf Badros ◽  
Marybeth Nelson ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase Ii ◽  
Single Agent ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Similar Treatment ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Best Response ◽  
Grade 3

Abstract INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM. METHODS: Patients who had at least one previous therapy for WM, symptomatic, and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15 q 28 days x 6 cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4. RESULTS: 17 pts (10 men and 7 women, median age 62 years, range 43 – 81) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. The median IgM at baseline was 4070 mg/dL (range 1370– 10,800); median M-spike at baseline was 2.48 g/dL (range 1.5 – 4.87); and median hemoglobin was 11.0 g/dL (6.3–15.2). The median follow up was 5 months (range 1 – 11 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. 13 pts are currently evaluable for response, best response to bortezomib and rituximab after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with bortezomib and rituximab. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6 and improved to grade 1 within 2 weeks of holding therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient. One patient discontinued therapy on study after 1 cycle because of inability to travel to study site and completed similar treatment off study and was unevaluable on this study. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates exciting activity achieving CR+ PR + MR in 85%, and/or stabilization of disease in 15% of evaluable patients with relapsed WM. No significant peripheral neuropathy was observed with this regimen. Updated data will be presented at the meeting. Response N=13; ORR (CR+PR+MR)= 85% Median time to best response (months) Complete Response 1 (8%) 6 Partial Response 3 (23%) 3.5 (3–4) Minimal Response 7 (54%) 4 (2–6) Stable Disease 2 (15%) NA Progressive Disease 0

Comparison Of Intermittent and Continuous Dosing Regimens Of Pomalidomide In Relapsed/Refractory Myeloma: Results Of A Phase II Randomized Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3205-3205
Author(s):  
Kartik Sehgal ◽  
Mehmet H. Kocoglu ◽  
Yanhong Deng ◽  
Rakesh Verma ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Response To Therapy ◽  
Phase Iii ◽  
Clinical Activity ◽  
Measurable Disease ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Maximal Reduction ◽  
Continuous Dosing

Abstract Pomalidomide (POM) is a novel IMiD(r) immunomodulatory agent with clinical activity in relapsed / resistant myeloma (RRMM) refractory to both lenalidomide and bortezomib. In prior phase II studies, the clinical activity of POM has been demonstrated using both continuous and intermittent dosing schedules. However the optimal dosing regimen for POM remains to be clarified and prospective data comparing these dosing schedules is limited. Herein we report the results of a randomized phase II clinical trial comparing the two POM dosing schedules. The primary objective was to compare clinical response to therapy (greater than or equal to partial response (PR) according to International Myeloma Working Group (IMWG) criteria). Patients (n=39) with RRMM documented to be refractory to lenalidomide were randomized to therapy with POM 2 mg/day for 28/28 days (Arm A, n=19) or POM 4 mg/day for 21/28 days (Arm B, n=20) of a 28 day cycle. All patients (pts) received POM alone at 2 or 4 mg for cycle 1, followed by the addition of dexamethasone at 40 mg weekly in subsequent cycles in both arms. Aspirin was utilized for thromboprophylaxis in both arms. Toxicity consisted primarily of myelosuppression which was manageable and similar in both cohorts. The incidence of serious adverse events (SAEs) was 36% in arm A and 55% in arm B. Grade 3 or 4 neutropenia (common toxicity criteria v4.0) was the most common toxicity and was observed in 42% and 45% of patients in arm A and arm B respectively. There was no treatment-emergent grade 3 or 4 neuropathy observed in either arm. Only one patient (in arm B) experienced grade 3 / 4 thromboembolic complication. Overall, objective response to therapy (greater than or equal to PR by IMWG criteria) was observed in 21% (4/19 patients) in arm A and 45% (9/20 patients) in arm B (p=0.18). There were no complete remissions in either cohort. Patients in arm B did have greater maximal reduction in measurable disease compared to arm A (percent maximal reduction mean (+ SD) 54% (+ 34%) in arm B versus 28% (+ 35%) in arm A, p=0.02). However both cohorts had comparable event-free survival (EFS) and overall survival (OS). The mean EFS in arm A and arm B was 4.4 months (95% confidence intervals (CI) 2.21 months, 7.67 months) and 5.1 months (95% CI 3.4 months, 9.2 months) respectively (p=0.56). Similarly the median OS in the arm A (17.7 months, 95% CI 10.02, not reached) was similar to that in arm B (17.7 months, 95% CI 9.98, not reached)(p=0.73). These data demonstrate in the context of a prospective randomized controlled clinical trial that both continuous (28/28) and intermittent (21/28) dosing regimens of POM with dexamethasone have remarkable clinical activity in this heavily pretreated MM population. These data provide further support towards the choice of POM at 4 mg/day for 21/28 days for phase III testing. The finding that intermittent dosing at 4 mg/day led to greater maximal cytoreduction of measurable disease compared to continuous dosing at 2 mg/day, without any differences in survival suggests that understanding the biology of residual disease will be essential to further improving outcome in these patients. Disclosures: No relevant conflicts of interest to declare.

GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Bart Neyns ◽  
Laila Ben Salama ◽  
Gil Awada ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Open Label ◽  
Grade 5 ◽  
Phase 2 Clinical Trial ◽  
Prior Surgery ◽  
Grade 3 ◽  
Tumor Types

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.

A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2654-2654 ◽  
Author(s):  
Gautam Borthakur ◽  
Susan O’Brien ◽  
Farhad Ravandi-Kashani ◽  
Francis Giles ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ambulatory Setting ◽  
Clinical Activity ◽  
Qtc Prolongation ◽  
Grade 3

Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. This Phase I trial was designed to evaluate the potential of prolonged infusions to minimize these toxicities while maintaining biological and clinical activity. We enrolled 14 patients at doses ranging from 7–40 mg/m2 over 24 hours every 2 weeks utilizing a modified accelerated titration design with 3–6 patients per cohort and doubling of the dose until 28 mg/m2. Cycle 1 was administered in a clinical research unit to accommodate PK sampling but subsequent cycles were administered in the ambulatory setting using portable infusion pumps. Median age was 62 (range 56–82) and 10 patients were male. The following diagnoses were included: myelodysplatic syndromes (MDS; 8, 4 secondary), refractory acute myelogenous leukemia (AML; 5) and CLL (1). A total of 51 infusions were administered. At doses ≤28 mg/m2, adverse events (AE) of Grade 1 dizziness (2/9), headache (2/9), euphoric mood (2/9) and Grade 2 somnolence (2/9) were of lesser frequency and intensity then at equivalent dose levels previously administered with a 3 hour infusion. At the 40 mg/m2 dose level, dose-limiting toxicities of Grade 3 QTc prolongation with no accompanying arrythmias were reported in 2/5 patients who both had QTc prolongation at baseline. Other toxicities included Grade 2 somnolence (4/5), Grade 1 euphoric mood (3/5), Grade 1 anxiety (2/5) and single reports of Grade 1 dizziness, dysarthria, dysphasia, confusion, hallucination and disorientation. The pharmacokinetics (PK) of obatoclax following a 24-hr IV infusion is dose proportional for both Cmax and AUC24h. Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA greater than 4-fold occurred in 10/14 patients by the midpoint of the infusion and was sustained to the end of the infusion. The rapid elimination of the plasma obatoclax concentration immediately following the end of infusion was associated with a decline of the plasma oligonucleosomal DNA level; however multiple additional peaks of oligonucleosomal DNA concentrations occurring over days following the infusion were still detected in 9 of 14 patients. 3/8 patients with MDS showed hematological improvement with red blood cell or platelet transfusion independence. Bone marrow blasts were reduced from 14% to 4% in another patient with secondary MDS. Conclusions: Single agent obatoclax is well tolerated when administered as a 24 hour continuous infusion, with abrogation of previously noted infusional CNS toxicities. Biological and clinical activity are retained. Further prolongation of the infusion may lead to more robust activity and will be explored. Phase II single agent trials using 28 mg/m2 over 24 hours every 2 weeks have been initiated in patients with myelofibrosis and previously untreated MDS with anemia and/or thrombocytopenia to further evaluate the potential for hematological improvement in response to obatoclax.

Phase I Results of Combination Gemcitabine and Bortezomib (Velcade®) for Relapsed/Refractory Nodal T-Cell Non-Hodgkin Lymphoma (T-NHL) and Aggressive B-Cell NHL (B-NHL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2005-2005 ◽  
Author(s):  
Andrew M. Evens ◽  
Leo I. Gordon ◽  
David Patton ◽  
Steven T. Rosen ◽  
Jane N. Winter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Single Agent ◽  
Dose Intensity ◽  
Clinical Activity ◽  
Repeated Treatment ◽  
Treatment Schedule ◽  
Cell Transplant ◽  
Grade 3

Abstract NF-κB is deregulated in several lymphoma subtypes, including aggressive B-NHL and T-NHL. The proteasome inhibitor, bortezomib, has the capacity to reverse some of the downstream consequences of NF-κB, but has only modest single-agent activity in aggressive NHL. Gemcitabine has a favorable toxicity profile and non-cross resistant mechanism of action with agents typically used in the first-line setting. Tumor cell lines and murine xenograft models demonstrate synergy between these two agents. Based on this data and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I trial of the combination to determine a dosing regimen for phase II investigation. The phase I design was a 3+3 dose escalation of bortezomib (1.3 mg/m2 and 1.6 mg/m2, day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on 21-day cycles. Following completion of bortezomib escalation, the phase II portion of the study was initiated. We report here the phase I study including toxicity and preliminary outcomes. 18 patients have enrolled, of whom 15 are evaluable for safety and preliminary efficacy. There were 8 women and 7 men, median age was 56 years (range 37–85 years), median prior therapies were 3 (range 2–5), and 67% had failed prior SCT. Histologies included diffuse large B-NHL (n=5) and T-NHL (1 hepatosplenic, 1 anaplastic, 2 angioimmunoblastic, 6 peripheral NOS). 11 pts accrued to the phase I portion. No dose limiting toxicity (DLT) was seen at bortezomib 1.3 mg/m2 (n=3 patients); 8 phase were tested at the next phase I dose level of bortezomib 1.6 mg/m2 since 2 patients experienced non-hematologic DLT (grade 3 hypertension and grade 3 liver function tests). The study continued to the phase II portion using bortezomib 1.6 mg/m2, in which 4 patients accrued. On planned analysis of the first 15 patients enrolled, it was noted that despite not meeting criteria for DLT, 10/15 patients experienced grade 3/4 neutropenia and/or thrombocytopenia resulting in repeated treatment delay(s). The median number of cycles delivered for all patients was 1 (range 1–3), while the median normalized dose-intensity was only 61%. Thus the trial was amended to institute a modified treatment schedule to administer gemcitabine and bortezomib on D1 and D15 on a 28-day schedule. Pre-planned analysis of the first 15 pts showed clinical activity/response allowing continuation of accrual onto the phase II portion (two partial remissions in T-NHL). In summary, our phase I study defined the safety/toxicity panel of combined bortezomib and gemcitabine dosing for patients with relapsed aggressive NHL. A planned analysis of the first 15 patients showed preliminary activity in heavily pre-treated patients allowing continuation to the 2nd stage, although repeated hematologic toxicities were seen leading to low dose intensity. Of note, data presented at ASCO 2008 (Luu et al. abstract #2563) studied the combination of bortezomib (D1, D4, D8, and D11) and gemcitabine (1,250 mg/m2 D1 and D8) in relapsed/ refractory advanced-stage solid tumors. The maximum tolerated dose of bortezomib there was 1.0 mg/m2 with gemcitabine. Furthermore, significant hematotoxicity was seen in that trial (grade 3/4 toxicity: 62% thrombocytopenia, 34% neutropenia, 17% anemia; with median of 2 cycles delivered). Accrual here continues to the phase II trial using a modified treatment schedule (gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 both D1 and D15 on a 28-day schedule) in order allow more consistent delivery of the intended therapy.

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