Aminosidine plus sodium stibogluconate for the treatment of Indian kala-azar: a randomized dose-finding clinical trial

Abstract Abstract 3580 Purpose: Bortezomib is a 26S proteasome inhibitor that is effective for the treatment of multiple myeloma and indolent lymphomas in adults. Bortezomib at a dose of 1.3 mg/m2 is well tolerated in pediatric patients as a single agent and in combination with cytotoxic chemotherapy. In vitro studies indicate that the proteasome inhibitor bortezomib sensitizes bulk myeloid leukemia and leukemia initiating cells (LIC) to chemotherapy. This Phase 2 study examined the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for relapsed pediatric acute myeloid leukemia (AML). Patients and Methods: This study was a two-arm, non-randomized, open label clinical trial in which patients received bortezomib twice weekly (1.3 mg/m2 on days 1, 4, and 8) in a 28-day cycle. Arm A (for patients with prior anthracycline exposure <400mg/m2) combined bortezomib with idarubicin (12 mg/m2 on days 1–3) and cytarabine (100mg/m2 on days 1–7). Arm B (for patients with prior anthracycline exposure >400 mg/m2) combined bortezomib with cytarabine (1000mg/m2 q12h on days 1–5) and etoposide (150 mg/m2on days 1–5). Arm B included an initial dose finding phase (n=12) which determined that bortezomib at 1.3 mg/m2/dose was safe to combine with cytarabine/etoposide. Bortezomib was then tested in a 2-stage efficacy phase for both arms. A second cycle of protocol therapy was allowed for patients with a response of at least stable disease. Results: The clinical trial enrolled a total of 52 patients for a total number of 61 cycles of therapy. Arm A enrolled 18 patients (16 eligible, 14 evaluable) and Arm B enrolled 34 patients (n=12 dose finding phase, n=22 efficacy phase (21 evaluable)) for a total of 24 patients evaluable for efficacy in Arm B. The addition of bortezomib to chemotherapy was tolerable in both arms. Severe toxicities included febrile neutropenia (29%) and transient hypokalemia (29%). Although tolerable, both Arm A and Arm B were closed after stage 1 of a two stage study design for failure to meet the efficacy threshold. Arm A response rate was 28% (3 CR and 1 CRp) and Arm B response rate was 42% (8 CR and 2 CRp). Although bortezomib was tolerated in both arms, response rates were adversely affected by a delay in neutrophil count recovery (ANC). Four patients in Arm A and 1 patient in Arm B had a complete response with delayed neutrophil recovery (CRi) which was considered a treatment failure in the study design. If a response of CRi had been included as a treatment success, both Arms A and B would have continued into the second stage of efficacy assessment. The 2-year overall survival (OS) for all evaluable patients was 35 ± 21%, and there was no difference in OS between the two treatment arms (Figure 1). Conclusion: Bortezomib is tolerable when added to chemotherapy regimens for children with relapsed/refractory or treatment-related AML. The overall response to the bortezomib containing chemotherapy regimens in the patients enrolled on the efficacy phase (CR + CRp + CRi) (50%) was similar to other salvage regimens for childhood acute myeloid leukemia. Bortezomib, however, did not improve either the CR rate or the OS of this patient cohort. Disclosures: Off Label Use: Testing of bortezomib for pediatric AML in the context of a phase 2 clinical trial.

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AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A Report from the Children’s Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.10003 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 10003-10003 ◽

Cited By ~ 5

Author(s):

Todd Michael Cooper ◽

Michael Absalon ◽

Todd Allen Alonzo ◽

Robert B Gerbing ◽

Kasey Joanne Leger ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Response Rate ◽

Residual Disease ◽

Complete Response ◽

Dose Finding ◽

Platelet Recovery ◽

Best Response ◽

First Relapse ◽

Grade 3

10003 Background: Effective regimens with favorable toxicity profiles are needed for heavily pre-treated children with relapsed AML. AAML1421 is a Phase I/II study of CPX-351, a liposomal preparation of cytarabine and daunorubicin demonstrating efficacy in adults. AAML1421 sought to determine the recommended Phase 2 Dose (RPD2) of CPX-351 and the response rate (complete response (CR) + complete response without platelet recovery (CRp)) after up to 2 cycles of therapy. Methods: Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding, and those in first relapse were eligible for efficacy. A modified rolling six design was used for dose-limiting toxicity (DLT) assessment which occurred in Cycle 1. Dose level 1 (DL1) was 135 units/m2 on days 1, 3, and 5 with a single dose de-escalation to 100 units/m2 if DL1 was intolerable. The Efficacy Phase used a Simon-two stage design. The response rate was determined after up to 2 cycles of therapy (Cycle 1: CPX-351; Cycle 2: FLAG). The Overall Response Rate (ORR) was defined as CR+CRp+CRi (CRi = CR with incomplete hematologic recovery). Results: Thirty-eight patients (pts) enrolled: 6 in dose-finding and 32 in the efficacy phase. DLT occurred in 1/6 patients and was a grade 3 decrease in ejection fraction(EF). This was the only Grade 3 cardiac toxicity. Therefore, 135 units/m2 on days 1, 3, 5 was the RP2D. All dose finding pts were eligible for efficacy determination. One pt in the efficacy phase was unevaluable. The most common ≥ Grade 3 toxicities in Cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 CR (54%), 5 CRp (14%), and 5 CRi (14%). Seventy percent achieved best response after cycle 1. Twenty-one of 25 patients with CR/CRp had no detectable residual disease (RD) (84%) by flow cytometry. HSCT was used as consolidation in 23/29 responders (79%); 18 of 23 (78%) had no detectable RD prior to HSCT. Conclusions: The RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, 5. CPX-351 was well tolerated and protocol therapy was effective with CR+CRp rates of 68.3% (90% CI 52.9% to 78.0%) and ORR (CR+CRp+CRi) of 81.1% (90% CI 67.4% to 88.8%). AAML1421 response rates are superior to any published North American cooperative group clinical trial for children with AML in first relapse. Clinical trial information: NCT02642965.

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Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.660 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 660-660 ◽

Cited By ~ 1

Author(s):

Rohan Garje ◽

James A. Brown ◽

Kenneth Gerard Nepple ◽

Laila Dahmoush ◽

Andrew Bellizzi ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Standard Dose ◽

Treatment Resistance ◽

Progression Free Survival ◽

Drug Uptake ◽

Dose Finding ◽

High Dose ◽

Cell Renal Cell Carcinoma ◽

Metastatic Rcc

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.

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First-in-human phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps3159 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS3159-TPS3159

Author(s):

Christian Diego Rolfo ◽

Soren Bentzen ◽

Martin Devenport ◽

Yang Liu ◽

Pan Zheng

Keyword(s):

Clinical Trial ◽

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Phase Ii ◽

Standard Dose ◽

Single Agent ◽

Stage Iv ◽

Dose Finding ◽

Treg Depletion ◽

Recommended Phase Ii Dose

TPS3159 Background: A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Our recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The irAEs are attributable to inactivation of the CTLA-4 checkpoint, while the CITE is effective through selective depletion of regulatory T cells (Treg) in the tumor microenvironment. We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. In preparation to test this ground-breaking hypothesis clinically, we have generated a next generation of anti-CTLA-4 antibody that preserves the CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4. The new antibody, ONC-392, has dramatically lower irAEs in a humanized mouse model and significantly more potent activity in depleting tumor-infiltrating Tregs, resulting in more effective CITE. Methods: This is an open label Phase IA/IB clinical study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients. The study consists of two linked parts: Part A is a dose-finding rapid titration study, with ONC-392 as a single agent in patients with advanced disease of various histology. The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M), Part B is a Phase IA/IB trial of ONC-392 in combination with a standard dose of 200 mg Pembrolizumab in patients with NSCLC. The trial consists of a dose-finding, dose escalation or de-escalation, Phase IA component aimed at defining the recommended phase II dose for ONC-392 in combination with a standard dose of Pembrolizumab (RP2D-C), then progressing into two parallel, single arm, Phase IB expansion cohorts to test for safety and initial efficacy in two groups of patients with NSCLC: Stage IV NSCLC anti-PD(L)1 immunotherapy naïve with PD-L1-positive (PD-L1 TPS ≥ 1%); Stage IV NSCLC refractory/resistant to anti-PD(L)1 immunotherapy. Clinical trial information: NCT04140526 .

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