UCHMC 1812: A phase 1b trial of CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myeloid leukemia.
Daria GautBradley CallasLloyd E. DamonBrian A. JonasDeepa JeyakumarCatherine BorrorStephanie OsorioTeresa TaSunmin ParkGary J. SchillerMatthew J. WieduwiltCaspian Oliai
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Abstract:
7024 Background: Gemtuzumab ozogamicin (GO) is effective in favorable-risk acute myelogenous leukemia (AML), while its activity is limited in higher-risk AML in part due to multi-drug resistance (MDR) mechanisms, particularly P-glycoprotein efflux pumps. CPX-351 provides a survival benefit in secondary AML, a disease characterized by high MDR activity. The objective of this trial is to utilize CPX-351 as a bulk cytoreduction agent, to first reduce the high MDR leukemia clones, followed by sequential treatment with GO in a more favorable leukemia environment. Methods: This was a multicenter phase Ib trial of CPX-351 plus GO in relapsed/refractory (R/R) AML patients with standard 3+3 dose escalation design (NCT03904251). Cohort A was treated with CPX-351 100 u/m 2 on days 1, 3, and 5 plus GO 3 mg/m 2 (max 4.5 mg) on day 7. Cohort B was treated with the same regimen plus an additional dose of GO 3 mg/m2 on day 4. The primary endpoint was the maximum tolerated dose (MTD), defined as < 2 dose limiting toxicities (DLTs) in the highest dose cohort. Secondary endpoints were IWG complete remission (CR) rate at day 28-42, liver veno-occlusive disease (VOD) rate diagnosed by the Baltimore criteria, and time of hematologic recovery (defined as ANC > 1000/uL and platelet count > 100,000/uL). Patients were enrolled at 4 University of California Hematologic Malignancies Consortium (UCHMC) centers: UC Los Angeles, UC San Francisco, UC Davis, and UC Irvine. Results: Thirteen participants were enrolled. The median age was 63 years (range 29-75). Eleven had relapsed disease, and two had refractory disease. Most received one prior line of therapy (n = 9). Seven had ELN 2022 adverse-risk disease at initial diagnosis, and two had intermediate-risk disease. The MTD was not reached. DLTs were observed in 1/6 participants in cohort A (grade 3 rash), and 1/6 participants in cohort B (grade 5 intracranial hemorrhage in the setting of severe thrombocytopenia). There were no cases of liver VOD. Of 12 evaluable participants, 4 achieved CR (33%), of whom 3 were negative for measurable residual disease by multiparametric flow cytometry, and 1 one achieved partial remission. The median age of responders was 30 years (range 28-65). The median time to return of normal hematopoiesis in those who achieved remission was 37 days (range 36-43). Three participants received allogeneic hematopoietic cell transplant (alloHCT) following investigational therapy: one remains in remission 34 months post-transplant, one died of infectious complications shortly after alloHCT, and one relapsed at day +60. Conclusions: CPX-351 plus two doses of GO 3 mg/m2 is a feasible treatment with acceptable toxicity and reasonable marrow recovery kinetics. However, only three participants went on to curative alloHCT. Further evaluation for efficacy in a larger patient population is needed to determine the utility of this regimen in R/R AML. Clinical trial information: NCT03904251 .Keywords:
Gemtuzumab ozogamicin
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Refractory (planetary science)
Gemtuzumab ozogamicin
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Calicheamicin
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It is difficult to decide an appropriate treatment strategy for elderly leukemia patients with other complications. We encountered 2 cases of refractory acute myeloid leukemia and safely treated the patients with fractionated administration of gemtuzumab ozogamicin (GO). Standard induction therapies were not effective for these patients. Moreover, they suffered from complications due to which their treatment options were restricted. Fractionated administration of GO (GO 3 mg/m(2) on days 1, 3 and 5) was accomplished safely and alleviated the patients' conditions. After treatment, these patients were followed by outpatient basis. We consider that this is an impressive treatment because fractionated administration of GO is potentially less toxic. Further, it will be helpful to maintain or improve the QOL of patients who are unable to receive intensive chemotherapy. These cases were significant because fractionated GO treatment is potentially less toxic and it will be helpful to maintain or improve the QOL of patients who can not receive intensive chemotherapy.
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Liu, Anthony Pak-Yin MBBS; Leung, Alex Wing-Kwan; Cheuk, Daniel Ka-Leung; Lee, Vincent; Ha, Shau-Yin Author Information
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Abstract Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.
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Read the full review for this Faculty Opinions recommended article: Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase 1/2 study.
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Objective: To explore a modified regimen which may improve complete remission rate and survival rate of patients with refractory leukemia.Methods: The prolonged CHAG regimen was used to cure 4 patients with refractory acute myeloid leukemia in order to observe curative effects and adverse reactions.Results: Four patients with refractory acute myeloid leukemia undergoing prolonged CHAG regimen achieved complete remission.Two of them died,but the rest survived,and one of them has survived for more than one year.Severe infection was not observed.There were no chemotherapy-related mortality or organ dysfunction.Conclusion: Prolonged CHAG regimen predicts a favorable curative effect with a high complete remission rate,and may be as an effective choice to patients with refractory leukemia.
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e19125 Background: AVAPER trial demonstrated that a bevacizumab, cisplatin and pemetrexed combination regimen (CDDP/PEM/BEV) is beneficial in advanced nonsquamous non-small-cell lung cancer (NS-NSCLC), but there are few reports of the regimen, which combined these agents. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in the treatment of NS-NSCLC with EGFR wild type in Japanese patients. Methods: Patients with stage III and IV NS-NSCLC with EGFR wild type were treated with CDDP/PEM/BEV. Chemotherapy treatments consisted of 4-6 cycles of CDDP 75mg/m2, pemetrexed 500mg/m2 and bevacizumab 15mg/kg on day 1 every 3 - 4 weeks. The primary endpoint of this study was the response rate and the secondary endpoint was PFS, OS and rates of adverse events. Results: Twenty-five patients were enrolled between August 2010 and February 2013. The patient’s demographics were: median age 62 years (range 42-70), 19 males and 6 females. 4 cases were stage III and 21 cases were stage IV. 22 (88%) Included EGFR wild type and 3 were unknown. The median number of cycles was 4 (range 1-6). 64% patients went to maintenance. Response rate (RR) was 64% and disease control rate (DCR) was 100%. The median progression free survival time was 10.3 months. Hematological adverse events reaching grade 3 to 4 were neutropenia (8%) with no febrile neutropenia, thrombocytopenia (4%), and anemia (4%). Nonhematological toxicities of grade 3/4 were hypertension (16%), infection (8%), hyponatremia (8%), thrombosis (4%), urticaria (4%), anorexia (4%), and hyperbilirubin (4%). Each of the toxicities were controllable and there were no treatment-related deaths. Conclusions: CDDP/PEM/BEV regimen is an effective and a tolerable regimen in patients with advanced NS-NSCLC with EGFR wild or unknown types. Clinical trial information: Is this clinical trial registered?.
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Objective
To explore the clinical effect of azacitidine combined with CAG regimen on the treatment of relapsed/refractory acute myeloid leukemia (AML).
Methods
The data of 50 patients with relapsed/refractory AML (non-acute promyelocytic leukemia) in Jining No. 1 People's Hospital from September 2018 to September 2019 was retrospectively analyzed, and the patients were divided into the control group and the test group according to the different treatment drugs. The control group (28 cases) was treated with CAG regimen alone, and the test group (22 cases) was treated with azacitidine combined with CAG regimen. The total effective rate and adverse reactions of the two groups were observed after 1 course of treatment.
Results
After one course of treatment, the total clinical effective rate in the test group was 86% (19/22), and the rate in the control group was 71% (20/28), there was a statistically significant difference between the two groups (χ 2 = 5.273, P 0.05).
Conclusion
Azacitidine combined with CAG regimen in the treatment of relapsed/refractory AML can improve the clinical efficacy without increasing the adverse reactions.
Key words:
Leukemia, myeloid, acute; Recurrence; Refractory; Azacitidine; CAG regimen
Azacitidine
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Clinical efficacy
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