scholarly journals Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

2021 ◽  
Vol 9 (12) ◽  
pp. e003645
Author(s):  
Victor Moreno ◽  
Maria-Pilar Barretina-Ginesta ◽  
Jesús García-Donas ◽  
Gordon C Jayson ◽  
Patricia Roxburgh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Escalation ◽  
Response Rate ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Cell Infiltration ◽  
Expansion Phase ◽  
Platinum Resistant ◽  
Phase 1B ◽  
Tumor Selective

BackgroundTreatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors.MethodsWe conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration.ResultsOverall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies.ConclusionsIntravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer.Trial registration numberNCT02028117.

scholarly journals Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial

2019 ◽  
Vol 20 (4) ◽  
pp. 570-580 ◽  
Author(s):  
Panagiotis A Konstantinopoulos ◽  
William T Barry ◽  
Michael Birrer ◽  
Shannon N Westin ◽  
Karen A Cadoo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Dose Escalation ◽  
Pi3k Inhibitor ◽  
Expansion Phase ◽  
Phase 1B

Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3069-3069 ◽  
Author(s):  
Margaret K. Callahan ◽  
Kunle Odunsi ◽  
Mario Sznol ◽  
John J. Nemunaitis ◽  
Patrick Alexander Ott ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Tumor Type ◽  
Open Label ◽  
Expansion Phase ◽  
Combination Methods

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD > 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]

Phase Ib trial of docetaxel, prednisone, and pazopanib, in men with metastatic castration resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 275-275
Author(s):  
Daniel J. George ◽  
Susan Halabi ◽  
Patrick Healy ◽  
Sarah Gemberling ◽  
Carolyn Winters ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dose Escalation ◽  
Objective Response Rate ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib

275 Background: Docetaxel prednisone (DP) is a standard of care for men with metastatic castrate resistant prostate cancer (mCRPC) with median progression-free survival (PFS) of 4-6 months and overall survival (OS) of 19 months, supporting a need for further treatment options. Pazopanib (PAZO) is a multi-targeted kinase inhibitor of VEGF receptors approved for treatment of kidney cancer and sarcoma. We performed a two center, Phase Ib study of DP + PAZO to evaluate the safety and early efficacy in mCRPC. Methods: This is a 2 site phase 1 DOD Prostate Cancer Clinical Trials Consortium trial of DP + PAZO once daily with ongoing ADT in men with mCRPC. The primary endpoint was safety; secondary endpoints included evaluation of a maximum tolerated dose (MTD) through a dose escalation and expansion design, pharmacokinetic assessments, PSA and radiographic responses, and toxicity. Results: Twenty-five men were treated over 6 dose levels using a 3+3 design. Pegfilgrastim (Neu) was added to the regimen after myelosuppression limited dose escalation. With Neu, our target MTD of D 75 mg/m2; P 10 mg QD and PAZO 800 mg QD was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. 17 patients had received prior Abi and/or Enza. The most common AEs were alopecia (86%), fatigue (69%), diarrhea (58%), and nausea (53%), and the most common Grade 3-5 SAEs were neutropenia (33%) and leukopenia (19%). Three deaths attributed to study treatment occurred: one from pneumonitis, one from respiratory failure, and one from intracranial hemorrhage. The proportion of 30%, 50% and 90 % PSA declines were 69%, 58% and 25%, respectively. The objective response rate was 31% (11/36). Median PFS was 18.6 months (95% CI: 6.5, 27.7) and OS was 22.2 months (95% CI: 14.7, -). Predicted median OS using the Halabi nomogram was 20.9 months (95% CI: 19.2, 23.0) with 23%, 34% and 43% of patients in low, intermediate and high risk groups, respectively. Conclusions: DP + PAZO (with Neu) were tolerable at full doses and demonstrated a surprisingly long PFS and high objective response rate in a relatively poor risk group of mCRPC patients. These data support further randomized studies of DP + Pazo in Abi/Enza refractory patients. Clinical trial information: NCT01385228.

Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 226-226 ◽  
Author(s):  
Ignacio Melero ◽  
Bruno Sangro ◽  
Thomas Cheung Yau ◽  
Chiun Hsu ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Immune Cell ◽  
Phase 1 ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Expansion Phase ◽  
Advanced Hcc

226 Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878.

scholarly journals Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial

2020 ◽  
Author(s):  
Gary L Gallia ◽  
Matthias Holdhoff ◽  
Henry Brem ◽  
Avadhut D Joshi ◽  
Christine L Hann ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Plasma Levels ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Newly Diagnosed ◽  
Kaplan Meier ◽  
High Grade Gliomas ◽  
Expansion Cohort

Abstract Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

CTNI-01. A PHASE 1-2 CLINICAL TRIAL OF EO1001 (APL-122), A NOVEL IRREVERSIBLE PAN-ERBB INHIBITOR WITH PROMISING BRAIN PENETRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Sophia Frentzas ◽  
Gary Richardson ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cns Metastases ◽  
Once Daily ◽  
Adult Participants ◽  
Xenograft Models ◽  
Cns Penetration

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. ESCALATION: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. EXPANSION: EO1001 will be administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.

1996 ◽  
Vol 14 (9) ◽  
pp. 2546-2551 ◽  
Author(s):  
E Bajetta ◽  
A Di Leo ◽  
L Biganzoli ◽  
L Mariani ◽  
F Cappuzzo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Confidence Interval ◽  
Cancer Patients ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Ca 125 ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
Exact Confidence Interval

PURPOSE The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease. PATIENTS AND METHODS Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases). RESULTS The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred. CONCLUSION VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.

scholarly journals 70. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE pan-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii14-ii15
Author(s):  
Helen Wheeler ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Harry Pedersen ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Single Dose ◽  
Dose Escalation ◽  
Rapid Development ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Erbb Receptors ◽  
Brain Penetration ◽  
Once Daily ◽  
Erbb Family ◽  
Cns Disease

Abstract CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥G2) is observed in the first dosing cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity is assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin's lymphoma.

1996 ◽  
Vol 14 (7) ◽  
pp. 2139-2144 ◽  
Author(s):  
A Saven ◽  
T Lee ◽  
M Kosty ◽  
L Piro
Keyword(s):  
Dose Escalation ◽  
Overall Response Rate ◽  
Response Rate ◽  
Opportunistic Infections ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Indolent Lymphoma ◽  
Dose Escalation Study ◽  
Overall Response ◽  
Major Activity

PURPOSE Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxantrone both exhibit major activity against indolent lymphoid malignancies and have different mechanisms of action, we performed a dose-escalation study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of this combination and to make preliminary observations about efficacy. PATIENTS AND METHODS Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escalations until dose-limiting toxicities (DLTs) were encountered. The initial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 days, mitoxantrone 5 mg/m2 intravenously (i.v.) on day 1, and prednisone 100 mg/d on days 1 to 5. Mitoxantrone was dose-escalated in increments of 2.5 mg/m2 i.v. on day 1. RESULTS The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m2 i.v. on day 1, and prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection were the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m2 i.v. on day 1; prednisone was omitted to decrease the risk of opportunistic infections. The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial responses (PRs). The median duration of CR was 15 months and PR 5 months. CONCLUSION These results demonstrate the feasibility and safety of combining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, and appear to confirm clinically the mechanistic synergism and rationale for this combination regimen. Prednisone exacerbated the risk of opportunistic infection and was omitted. The overall response rate was high, including durable CRs. Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma.

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