Summary
Background
Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitors are efficacious in B-cell malignancies. Immune-related adverse events might be mitigated with intermittent dosing. We aimed to evaluate the safety and antitumour activity of zandelisib, a potent novel PI3Kδ inhibitor, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy.
Methods
We conducted a first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA. Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy (limited to follicular lymphoma or chronic lymphocytic leukaemia during dose escalation) and an Eastern Cooperative Oncology Group performance status of 0–2, and had received at least one previous line of therapy and no previous PI3Kδ inhibitor treatment. In the dose-escalation study, participants received oral zandelisib once daily (60 mg, 120 mg, or 180 mg; we did not evaluate four additional planned dose levels). The 60 mg dose was further evaluated as monotherapy or with intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3–6, using a continuous daily schedule or intermittent dosing therapy (days 1–28 of cycles 1–2 and days 1–7 of subsequent cycles) in 28-day cycles. Treatment was continued until evidence of disease progression, intolerance, or withdrawal of consent by the patient. Primary endpoints were safety (dose-limiting toxicities and maximum tolerated dose), minimum biologically effective dose, and a composite endpoint to assess the activity of each dose level, and were analysed by intention to treat. The zandelisib monotherapy and zandelisib–rituximab combination cohorts have completed accrual, but accrual to a cohort evaluating zandelisib with zanubrutinib is ongoing. This study is registered with ClinicalTrials.gov, NCT02914938.
Findings
Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and received zandelisib monotherapy (n=56) or zandelisib plus rituximab (n=41), with zandelisib administered on either a continuous schedule (n=38) or with intermittent dosing (n=59). No dose-limiting toxicities were observed, the objective of determining the maximum tolerated dose was abandoned, and antitumour activity was similar across the evaluated doses activity (objective responses in 11 [92%; 95% CI 61·5–99·8] of 12 patients at both 60 mg and 120 mg doses, and in five [83%; 95% CI 35·9–99·6] of six patients at 180 mg). With a median duration of exposure of 15·2 months (IQR 3·7–21·7), the most common grade 3–4 adverse events were neutrophil count decrease (ten [17%] of 59 patients in the intermittent dosing group and four [11%] of 38 in the continuous dosing group), diarrhoea (three [5%] and eight [21%]), pneumonia (one [2%] and six [16%]), alanine aminotransferase increase (three [5%] and two [5%]), and colitis (two [3%] and one [3%]). 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3–4 adverse events. Treatment-related serious adverse events occurred in eight (21%) patients in the continuous dosing group and five (8%) patients in the intermittent dosing group. There were no treatment-related deaths.
Interpretation
Zandelisib 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase 2 and phase 3 trials.
Funding
MEI Pharma.
Introduction
Phosphatidylinositol 3-kinase p110δ (PI3Kδ) is essential in B-cell signalling, including for homing, adhesion, proliferation, and survival.1–3 PI3Kδ inhibitors, administered as monotherapy or with anti-CD20 antibodies, have antitumour activity in chronic lymphocytic leukaemia (or small lymphocytic lymphoma), follicular lymphoma, and marginal zone lymphoma.4–9 However, PI3Kδ inhibitors are associated with immune-mediated adverse events, which are thought to be caused by chronic on-target suppression of regulatory T cells10 and have therefore limited the use of PI3Kδ inhibitors in clinical practice.11,12 There is a need to develop novel PI3Kδ inhibitors with improved safety and efficacy profiles.
Zandelisib is an orally bioavailable, potent, novel, selective PI3Kδ inhibitor, with a molecular structure that is distinct from other PI3Kδ inhibitors.13 Its plasma half-life (28 h) permits daily dosing. In-vitro target binding of 5 h or longer and high volume of distribution predicted prolonged target inhibition in patients and higher tissue exposure relative to plasma.14,15 We hypothesised that zandelisib could be administered on an intermittent dosing schedule designed to facilitate regulatory T-cell repopulation, thereby reducing immune-mediated adverse events associated with continuous PI3Kδ inhibition, without loss of efficacy. Basophil activation test assay results from a phase 1 study in healthy volunteers predicted that daily dosing at 60 mg would lead to trough plasma concentrations resulting in at least 90% PI3Kδ inhibition, and informed the starting dose in our study.15
We aimed to evaluate the safety and antitumour activity of zandelisib, with continuous or intermittent dosing as monotherapy or in combination with rituximab, in patients with relapsed or refractory B-cell malignancy.
Methods
Study design and participants
We conducted an open-label, first-in-patient, dose-escalation and dose-expansion, phase 1b trial at ten treatment centres across Switzerland and the USA (appendix p 15). Eligible patients were aged 18 years or older with relapsed or refractory B-cell malignancy, Eastern Cooperative Oncology Group performance status of 0–2, and adequate renal function (serum creatinine ≤1·5 times the upper limit of normal [ULN] or estimated glomerular filtration rate >50 mL/min) and hepatic function (aminotransferases ≤2·0 times the ULN and total bilirubin ≤2·0 times the ULN), and adequate haematological parameters (haemoglobin ≥5·6 mmol/L, absolute neutrophil count ≥1·0 × 109/L, platelet count >75 × 109/L unless due to chronic lymphocytic leukaemia or follicular lymphoma). Patients were required to have received at least one previous systemic therapy for their B-cell malignancy and have disease progression requiring therapy according to the investigator. We excluded patients who had active hepatitis B virus or hepatitis C virus infection (occult or previous hepatitis B virus infection with undetectable DNA was permitted with prophylaxis), major surgery within the previous 4 weeks, uncontrolled concurrent medical problems, history of myocardial infarction or heart failure of New York Heart Association classification 2 or higher within the previous 6 months, drug-induced pneumonitis, other diagnosis of cancer that was likely to require treatment in the next 2 years (curatively treated basal cell carcinoma or squamous cell carcinomas of the skin, carcinoma in-situ of the cervix, and hormonal therapy for prostate cancer were permitted), previous PIK3δ inhibitor therapy, or previous progressive disease on Bruton’s tyrosine kinase (BTK) inhibitor therapy. Additional eligibility criteria are listed in the protocol (appendix).
This study was approved by the institutional review boards or ethics committees at all participating sites and was done in accordance with the principles of the Declaration of Helsinki and the Guidelines for Good Clinical Practice. All patients provided written, informed consent to participate.
Procedures
We developed an intermittent dosing schedule (referred to as intermittent dosing therapy) with zandelisib administered on days 1–28 of cycles 1 and 2 for initial tumour debulking then on days 1–7 of each subsequent 28-day cycle, incorporating a 21-day treatment break for drug elimination (7 days) and regulatory T-cell repopulation (14 days).16 Dose escalation used a continual reassessment method to establish the minimum biologically effective dose, maximum tolerated dose (if applicable), safety, pharmacokinetics, and preliminary activity of zandelisib in relapsed follicular lymphoma and chronic lymphocytic leukaemia or small lymphocytic lymphoma. Dose escalation was limited to these two disease entities because published studies with other PI3Kδ inhibitors in follicular lymphoma and chronic lymphocytic leukaemia or small lymphocytic lymphoma provided information about the acceptable response rates in these tumours, which were used in the continual reassessment method model parameters. After the recommended phase 2 dose was established, zandelisib was evaluated in two parallel expansion cohorts, as monotherapy in patients with relapsed or refractory follicular lymphoma and chronic lymphocytic leukaemia or small lymphocytic lymphoma, and in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma not otherwise specified, or high-grade B-cell lymphoma, as defined by WHO.17
Zandelisib was administered orally in 28-day cycles at a starting dose of 60 mg once daily. Patients were assessed during cycles 1 and 2 (56 days) of continuous therapy for dose-limiting toxicities, defined as grade 3 or worse non-haematological toxicities or grade 4 haematological toxicities (growth factor support permitted), or any toxicity resulting in treatment discontinuation during the dose-limiting toxicity assessment period. The 56-day dose-limiting toxicity assessment period was selected to capture early grade 3 or worse increases in aminotransferases that were reported as dose-limiting toxicities with other PI3Kδ inhibitors. Patients were evaluable for dose-limiting toxicity assessment if they completed the assessment period and received at least 75% of their zandelisib doses during this period, or discontinued earlier due to toxicity. Patients who discontinued during the dose-limiting toxicity assessment period for reasons other than toxicity (disease progression or withdrawal of consent) were replaced. The zandelisib dose was escalated using a continual reassessment method model with seven planned dose levels (60–780 mg once daily on days 1–28 of each 28-day cycle), with six patients treated at each dose level for preliminary efficacy assessment.18,19 The maximum tolerated dose was the highest dose that was safe (dose-limiting toxicity rate closest to 0·25). For each dose level deemed safe per the continual reassessment method model that met prespecified preliminary efficacy criteria, up to 12 patients could be enrolled to further assess safety and activity.
After dose escalation, we defined the recommended phase 2 dose as 60 mg once daily. Subsequent patients were enrolled into two parallel cohorts to evaluate zandelisib monotherapy or zandelisib in combination with rituximab, using either daily continuous schedule dosing or intermittent dosing therapy (days 1–28 of cycles 1–2 and days 1–7 of subsequent 28-day cycles). In the cohort assigned to receive combination therapy, rituximab was administered by intravenous infusion at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3–6. In all cohorts, zandelisib was administered until disease progression or intolerance, and patients were discontinued from the study after treatment termination or withdrawal of consent. Patients with progressive disease while receiving zandelisib on intermittent dosing therapy had the option to transition to continuous daily dosing at 60 mg to recapture response. Patients who discontinued zandelisib due to toxicity were followed up until resolution of the event and then discontinued from the study. Zandelisib was withheld for grade 2 non-infectious pneumonitis and grade 3 non-haematological toxicities, and upon resolution of the toxicity to grade 1 or better, zandelisib was resumed at 60 mg on intermittent dosing for patients in the 60 mg cohort or at a lower dose level for patients in the 120 mg and 180 mg cohorts. Zandelisib was discontinued for any grade 4 non-haematological toxicities. Zandelisib was withheld for grade 4 thrombocytopenia or grade 4 neutropenia with symptoms, until resolution to grade 3 or better.
Patients received prophylaxis for Pneumocystis jirovecii pneumonia (sulfamethoxazole–trimethoprim or atovaquone preferred) and had serial monitoring for cytomegalovirus. Growth factor support (pegfilgrastim or filgrastim) was permitted.
The continuous schedule dosing group was comprised of all patients enrolled with intent to administer zandelisib on a continuous daily regimen, and included those who were transitioned to intermittent dosing in cycle 4 or later after a protocol amendment introduced intermittent dosing on Jan 2, 2018. The intermittent dosing therapy group was comprised of all patients enrolled with intent to administer zandelisib using the intermittent dosing schedule.
All patients who were enrolled and treated in the study were evaluable for toxicity. Toxicity assessment was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 and included history, vital signs, and physical examination on all days of treatment, and laboratory monitoring including haematology and serum chemistries (weekly during month 1, once every 2 weeks during month 2, monthly during months 3–7, once every 2 months during months 7–13, and once every 3 months thereafter). Investigator-based response assessments by CT with or without 18F-fluorodeoxyglucose-PET imaging, in accordance with Lugano Classification response criteria for B-cell lymphoma20 and International Workshop on Chronic Lymphocytic Leukemia guidelines,19 were done after cycles 2 and 6 of therapy, then every 6 months thereafter.
Blood samples to evaluate the pharmacokinetics of zandelisib monotherapy and zandelisib in combination with rituximab were collected on days 1, 7, 14, 21, and 28 and, for patients receiving zandelisib intermittent dosing therapy, on day 62 of treatment (last day of cycle 3) and days 63–69 (first 7 days of cycle 3 drug holiday) when no drug was administered to evaluate the terminal-phase pharmacokinetic parameters.
Outcomes
The primary endpoints of the dose-escalation study of zandelisib monotherapy were to assess safety and tolerability and determine the minimum biologically effective dose (dose defined as a dose with dose-limiting toxicity rate closest to 25% that showed an overall response rate of ≥30% in up to 12 patients within 8 weeks), maximum tolerated dose (defined as the highest dose that is safe with dose-limiting toxicity rate closest to 25%), and dose-limiting toxicities of zandelisib monotherapy in patients with relapsed or refractory follicular lymphoma, or chronic lymphocytic leukaemia or small lymphocytic lymphoma. The objective of defining the maximum tolerated dose of zandelisib was abandoned because dose escalation was closed due to the high overall response rates observed at the initial three doses levels evaluated, without dose-limiting toxicities observed at any dose level studied.
The primary endpoint of the expansion cohort of zandelisib and rituximab was to assess the safety and tolerability of the combination of zandelisib and rituximab in patients with relapsed or refractory B-cell malignancies. The primary safety endpoints were reviewed centrally by the safety review committee, consisting of investigators and the study funder. Secondary endpoints were the safety profile, overall response rate, complete response rate, minimal residual disease in chronic lymphocytic leukaemia with 1 × 10−4 cells threshold by flow cytometry, duration of response, progression-free survival, pharmacokinetics, and recommended phase 2 dose (dose selected for further evaluation in later-stage trials) of zandelisib administered as monotherapy or in combination with rituximab. Pharmacokinetics is not reported here because exposure-response analysis is still ongoing. Minimal residual disease analysis is still ongoing and will be reported elsewhere.
Statistical analysis
During dose escalation, the sample size was based on continual reassessment method model simulations, and six to 12 patients were required per dose level to obtain adequate safety and preliminary efficacy data to establish the minimum biologically effective dose. A sequential probability ratio test with overall response rate at 8 weeks of less than 30% versus overall response rate at 8 weeks of 50% or greater with a type I error of 0·20 and type II error of 0·15 was used to test if each dose was efficacious or not. The sample size in the 60 mg monotherapy cohort was 42 patients, with the proposition that an observed overall response rate of 60% would justify further development. The sample size in each of the zandelisib plus rituximab cohorts was 24 patients, with the proposition that an observed overall response rate of 75% in patients with chronic lymphocytic leukaemia or indolent lymphoma and 30% in patients with diffuse large B-cell lymphoma or high-grade lymphoma would justify further development. Additional details regarding the expansion cohorts are provided in the protocol (appendix). The data cutoff date for this report was Sept 15, 2020.
Responses, as determined according to investigator assessment with no central review, were analysed by intention to treat and summarised descriptively. All patients who had an 8-week response assessment, or had disease progression before 8 weeks, were included in the efficacy analyses. Frequencies and proportions of best overall response and complete response were calculated, along with the exact 95% CI (Clopper-Pearson method). Progression-free survival and duration of response were calculated using the Kaplan-Meier method from treatment start (for progression-free survival) or time of initial response (for duration of response) to disease progression or death. Safety was analysed in all patients who received at least one dose of zandelisib. Cumulative hazard for time to first grade 3 adverse event of special interest was calculated using the Kaplan-Meier method. No sensitivity analyses were performed. We did a post-hoc subgroup analysis of patients who were refractory or relapsed to rituximab. Statistical analyses were performed using SAS (version 9.3). This study is registered with ClinicalTrials.gov, NCT02914938.
Role of the funding source
The study funder and investigators jointly designed the study and collected, analysed, and interpreted the data, and wrote the manuscript.
Results
Between Nov 17, 2016, and June 2, 2020, 100 patients were assessed for eligibility and 97 were enrolled and treated (figure 1), including 31 in the dose-escalation cohorts and 66 in the expansion cohorts. Baseline demographics and clinical characteristics are shown in table 1. Baseline characteristics were similar between the continuous schedule dosing and intermittent dosing therapy groups (appendix pp 6–7).
Figure 1:
Trial profile
Table 1:
Baseline characteristics by disease type
| Follicular lymphoma (n=63) | Chronic lymphocytic leukaemia or small lymphocytic lymphoma (n=21) | Marginal zone lymphoma (n=4) | Diffuse large B-cell lymphoma (n=9) | All patients (n=97) | |
|---|---|---|---|---|---|
|
| |||||
| Age, years | |||||
| Median (IQR) | 64·0 (56·0-72·0) | 67·0 (57·0-72·0) | 72·5 (71·0-83·5) | 69·0 (65·0-79·0) | 65·0 (57·0-73·0) |
| ≥65 | 31 (49%) | 12 (57%) | 4 (100%) | 7 (78%) | 54 (56%) |
| Sex | |||||
| Male | 43 (68%) | 15 (71%) | 0 | 5 (56%) | 63 (65%) |
| Female | 20 (32%) | 6 (29%) | 4 (100%) | 4 (44%) | 34 (35%) |
| Race | |||||
| Asian | 2 (2%) | 0 | 0 | 0 | 2 (2%) |
| Black | 2 (3%) | 2 (10%) | 0 | 0 | 4 (4%) |
| White | 59 (94%) | 19 (90%) | 4 (100%) | 9 (100%) | 91 (93%) |
| Previous anti-lymphoma therapy | |||||
| Median number of previous therapies (IQR) | 2·0 (1·0-3·0) | 1·0 (1·0-2·0) | 1·0 (1·0-1·0) | 2·0 (2·0-3·0) | 2·0 (1·0-3·0) |
| ≥2 previous therapies | 35 (56%) | 9 (43%) | 0 | 8 (89%) | 52 (54%) |
| Anti-CD20 use | 62 (98%) | 17 (81%) | 4 (100%) | 9 (100%) | 92 (95%) |
| Refractory to anti-CD20 antibody therapy* | 26 (41%) | 3 (14%) | 2 (50%) | 8 (89%) | 39 (40%) |
| Refractory to most recent therapy* | 24 (38%) | 5 (24%) | 1 (25%) | 6 (67%) | 36 (37%) |
Data are n (%) unless otherwise stated.
Refractory was defined as no response with treatment or relapsed on previous treatment within 6 months after most recent therapy.
During dose escalation, 31 patients with follicular lymphoma or chronic lymphocytic leukaemia or small lymphocytic lymphoma received zandelisib at dose levels of 60 mg (13 patients; one withdrew consent during cycle 1 and was not evaluable for dose-limiting toxicities), 120 mg (12 patients), and 180 mg (six patients; figure 1). No dose-limiting toxicities were observed. Dose escalation was terminated at 180 mg due to the similarly high response rates and safety profiles between tested dose levels (appendix pp 8–9), thus the maximum tolerated dose was not defined. As such, 60 mg was declared as both the minimum biologically effective dose as well as the recommended phase 2 dose for further evaluation, on the basis of preliminary assessments of safety, anti-lymphoma activity, and trough plasma concentrations exceeding the 90% effective concentration (basophil activation test) for all patients who received the 60 mg dose (data not shown).
Among the 97 patients who were enrolled, 56 received zandelisib monotherapy and 41 received zandelisib plus rituximab. 59 patients received zandelisib as intermittent dosing therapy and 38 received continuous schedule dosing (33 with zandelisib monotherapy and five with zandelisib plus rituximab; figure 1). 21 (55%) of 38 patients in the continuous schedule dosing group who were still on the study treatment as of Jan 2, 2018, were switched to intermittent dosing after a median of seven cycles (IQR 6–9); the other 17 patients discontinued therapy before intermittent dosing was implemented and therefore received only continuous dosing.
Among 97 evaluable patients, 58 (60%) discontinued therapy. As of the data cutoff date (Sept 15, 2020), 39 (40%) of 97 patients were still on treatment (ten [26%] in the continuous dosing group and 29 [49%] in the intermittent dosing group; figure 1; appendix pp 2, 10). The median treatment duration for all patients was 10·4 months (IQR 2·9–33·1) in the continuous dosing group and 15·2 months (4·8–20·0) in the intermittent dosing group (appendix p 11), and for patients still on therapy, the median exposure durations were 35·9 months (IQR 33·9–42·3) in the continuous dosing group and 18·6 months (17·5–27·3) in the intermittent dosing group.
Safety was assessed in all 97 patients. Adverse events that occurred in at least 10% of patients, regardless of attribution to therapy, are presented by zandelisib dosing schedule in table 2. 26 (44%) of 59 patients in the intermittent dosing group and 29 (76%) of 38 patients in the continuous dosing group had grade 3–4 adverse events. With a median duration of exposure of 15·0 months (IQR 3·7–21·7), the most common grade 3 or worse adverse events were neutrophil count decrease (14 [14%] of 97 patients), diarrhoea (11 [11%]), pneumonia (seven [7%]), alanine aminotransferase (ALT) increase (five [5%]), and colitis (three [3%]). Treatment was interrupted due to adverse events in 15 (39%) of 38 patients in the continuous dosing group and 26 (44%) of 59 in the intermittent dosing group. Serious adverse events were reported in 13 (34%) of 38 patients receiving continuous dosing and 13 (22%) of 59 patients receiving intermittent dosing. Treatment-related serious adverse events were reported in eight (21%) of 38 patients in the continuous dosing group and five (8%) of 59 patients in the intermittent dosing group. The most common treatment-related serious adverse events (that occurred in two or more patients) were pneumonia (n=3) and diarrhoea (n=2) in the continuous dosing group, and colitis (n=3) and pneumonitis (n=2) in the intermittent dosing group.
Table 2:
Treatment-emergent adverse events and adverse events of special interest
| Continuous dosing group (n=38) |
Intermittent dosing group (n=59)* |
|||||
|---|---|---|---|---|---|---|
| Grade 1–2 | Grade 3 | Grade 4 | Grade 1–2 | Grade 3 | Grade 4 | |
|
| ||||||
| Treatment-emergent adverse events | ||||||
| Diarrhoea | 10 (26%) | 8 (21%) | 0 | 24 (41%) | 3 (5%) | 0 |
| Fatigue | 13 (34%) | 0 | 0 | 17 (29%) | 1 (2%) | 0 |
| Cough | 11 (29%) | 0 | 0 | 18 (31%) | 0 | 0 |
| Rash maculopapular | 11 (29%) | 0 | 0 | 7 (12%) | 3 (5%) | 0 |
| Arthralgia | 8 (21%) | 1 (3%) | 0 | 7 (12%) | 1 (2%) | 0 |
| AST increased | 8 (21%) | 1 (3%) | 0 | 14 (24%) | 1 (2%) | 0 |
| Decreased appetite | 9 (24%) | 0 | 0 | 4 (7%) | 1 (2%) | 0 |
| Nausea | 8 (21%) | 1 (3%) | 0 | 18 (31%) | 0 | 0 |
| Abdominal pain | 8 (21%) | 0 | 0 | 10 (17%) | 0 | 0 |
| Gastroesophageal reflux disease | 8 (21%) | 0 | 0 | 4 (7%) | 0 | 0 |
| Nasal congestion | 8 (21%) | 0 | 0 | 8 (14%) | 0 | 0 |
| Productive cough | 8 (21%) | 0 | 0 | 8 (14%) | 0 | 0 |
| Pyrexia | 7 (18%) | 1 (3%) | 0 | 8 (14%) | 0 | 0 |
| ALT increased | 5 (13%) | 2 (5%) | 0 | 9 (15%) | 3 (5%) | 0 |
| Constipation | 7 (18%) | 0 | 0 | 6 (10%) | 0 | 0 |
| Oedema peripheral | 6 (16%) | 1 (3%) | 0 | 13 (22%) | 0 | 0 |
| Platelet count decreased | 6 (16%) | 0 | 1 (3%) | 14 (24%) | 0 | 0 |
| Pneumonia | 1 (3%) | 6 (16%) | 0 | 2 (3%) | 1 (2%) | 0 |
| Anaemia | 4 (11%) | 1 (3%) | 1 (3%) | 5 (8%) | 1 (2%) | 0 |
| Blood creatinine increased | 5 (13%) | 1 (3%) | 0 | 11 (19%) | 1 (2%) | 0 |
| Dry mouth | 6 (16%) | 0 | 0 | 4 (7%) | 0 | 0 |
| Neutrophil count decreased | 2 (5%) | 3 (8%) | 1 (3%) | 2 (3%) | 8 (14%) | 2 (3%) |
| Stomatitis | 5 (13%) | 1 (3%) | 0 | 1 (2%) | 0 | 0 |
| Upper respiratory tract infection | 6 (16%) | 0 | 0 | 4 (7%) | 1 (2%) | 0 |
| Dyspnoea | 5 (13%) | 0 | 0 | 2 (3%) | 2 (3%) | 0 |
| Electrocardiogram QT prolonged | 4 (11%) | 0 | 1 (3%) | 3 (5%) | 0 | 0 |
| Headache | 5 (13%) | 0 | 0 | 7 (12%) | 1 (2%) | 0 |
| Hypertension | 3 (8%) | 2 (5%) | 0 | 2 (3%) | 0 | 0 |
| Insomnia | 3 (8%) | 2 (5%) | 0 | 3 (5%) | 0 | 0 |
| Rash | 3 (8%) | 2 (5%) | 0 | 4 (7%) | 0 | 0 |
| Upper airway cough syndrome | 5 (13%) | 0 | 0 | 1 (2%) | 0 | 0 |
| Back pain | 4 (11%) | 0 | 0 | 6 (10%) | 0 | 0 |
| Blood bilirubin increased | 4 (11%) | 0 | 0 | 1 (2%) | 0 | 0 |
| Dizziness | 4 (11%) | 0 | 0 | 8 (14%) | 0 | 0 |
| Dry skin | 4 (11%) | 0 | 0 | 1 (2%) | 0 | 0 |
| Ear pain | 4 (11%) | 0 | 0 | 2 (3%) | 0 | 0 |
| Fall | 4 (11%) | 0 | 0 | 2 (3%) | 1 (2%) | 0 |
| Hyperkalaemia | 4 (11%) | 0 | 0 | 8 (14%) | 0 | 0 |
| Malaise | 4 (11%) | 0 | 0 | 1 (2%) | 0 | 0 |
| Urinary tract infection | 4 (11%) | 0 | 0 | 6 (10%) | 0 | 0 |
| Vomiting | 3 (8%) | 1 (3%) | 0 | 6 (10%) | 0 | 0 |
| Weight decreased | 3 (8%) | 1 (3%) | 0 | 4 (7%) | 0 | 0 |
| Hypokalaemia | 1 (3%) | 2 (5%) | 0 | 6 (10%) | 1 (2%) | 1 (2%) |
| Pain in extremity | 3 (8%) | 0 | 0 | 11 (19%) | 0 | 0 |
| Hyperglycaemia | 0 | 2 (5%) | 0 | 9 (15%) | 1 (2%) | 0 |
| Lymphocyte count decreased | 2 (5%) | 0 | 0 | 7 (12%) | 1 (2%) | 0 |
| Hyponatraemia | 2 (5%) | 0 | 0 | 3 (5%) | 3 (5%) | 0 |
| Abdominal distension | 1 (3%) | 0 | 0 | 6 (10%) | 0 | 0 |
| Blood alkaline phosphatase increased | 0 | 1 (3%) | 0 | 8 (14%) | 1 (2%) | 0 |
| Infusion-related reaction | 1 (3%) | 0 | 0 | 6 (10%) | 0 | 0 |
| Pruritus | 1 (3%) | 0 | 0 | 7 (12%) | 0 | 0 |
| Adverse events of special interest | ||||||
| Diarrhoea or colitis | 9 (24%) | 9 (24%) | 0 | 22 (37%) | 5 (8%) | 0 |
| Rash, all types | 12 (32%) | 2 (5%) | 0 | 14 (24%) | 3 (5%) | 0 |
| ALT or AST elevation | 8 (21%) | 2 (5%) | 0 | 13 (22%) | 3 (5%) | 0 |
| Lung infection or pneumonia | 1 (3%) | 6 (16%) | 0 | 2 (3%) | 1 (2%) | 0 |
| Mucositis | 6 (16%) | 1 (3%) | 0 | 1 (2%) | 0 | 0 |
| Non-infectious pneumonitis | 0 | 0 | 0 | 1 (2%) | 1 (2%) | 0 |
Data are n (%), n is number of patients. Treatment-emergent adverse events that occurred in at least 10% of patients in either group, irrespective of causality, are shown and listed in order of decreasing frequency in the continuous dosing group. All adverse events of special interest are shown. Patients in the continuous dosing group had continuous daily dosing after cycle 3 and were switched to the intermittent dosing group following a protocol amendment. In the intermittent dosing group, patients received two cycles of daily dosing followed by dosing on days 1–7 from cycle 3 onwards in 28 day cycles. Adverse events did not increase with the addition of rituximab (appendix pp 9, 12); therefore, the zandelisib monotherapy and zandelisib plus rituximab groups are presented together. ALT=alanine aminotransferase. AST=aspartate aminotransferase.
One grade 5 treatment-emergent adverse event occurred in the intermittent dosing group (due to COVID-19).
Grade 3 or worse adverse events of special interest occurred more frequently in the continuous dosing group than in the intermittent dosing group (eg, grade 3 diarrhoea or colitis in nine [24%] of 38 patients vs five [8%] of 59, and grade 3 lung infection in six [16%] vs one [2%] of 59; table 2). Grade 3 or worse aspartate aminotransferase or ALT elevation (two [5%] vs three [5%]) and rash (two [5%] vs three [5%]) were uncommon with both dosing schedules. There was a continued increased risk of grade 3 diarrhoea or colitis in the continuous dosing group (median time to occurrence of 120 days [range 54–285], with seven of nine cases reported in cycle 4 or later), compared with a decreased risk over time in the intermittent dosing group (median time to occurrence of 73 days [range 30–457], with one of five cases reported in cycle 4 or later). At a median follow-up of 24·9 months (95% CI 6·5–33·9) in the continuous dosing group and 15·7 months (95% CI 10·4–17·9) in the intermittent dosing group, the cumulative incidence of grade 3 or worse adverse events of special interest was 45% (17 of 38 patients) in the continuous dosing group and 20% (12 of 59) in the intermittent dosing group, with decreasing cumulative hazard rate in the intermittent dosing group after switching to intermittent dosing (figure 2; appendix p 13).
Figure 2:
Kaplan-Meier estimate of time to first grade 3 or worse adverse event of special interest, by dosing schedule
In the continuous dosing group, six (16%) of 38 patients discontinued treatment due to adverse events after a median of 6·7 months (IQR 4·8–10·3), including rash (n=2), arthritis (n=1), cardiomyopathy (n=1), drug intolerance (n=1), and diarrhoea (n=1; appendix p 10). In the intermittent dosing group, six (10%) of 59 patients discontinued treatment due to adverse events after a median of 3·2 months (IQR 2·6–8·8), including diarrhoea (n=3), pneumonitis (n=1), rash (n=1), and fungal infection (n=1). One grade 5 adverse event occurred in a patient in the intermittent dosing group who died from COVID-19, which was not deemed to be related to treatment. There were no treatment-related deaths.
Two patients discontinued treatment before the first disease assessment and were not included in the efficacy evaluable population (one with follicular lymphoma who withdrew consent in cycle 1 and one with chronic lymphocytic leukaemia due to an adverse event). Investigator-assessed overall responses and complete responses for patients treated with zandelisib alone or in combination with rituximab and by lymphoma type and dosing schedule are shown in table 3. 48 (77%) of 66 patients with indolent B-cell malignancy had an initial response on the first imaging scan on day 56 (appendix p 14). The overall response rate was similar in the three dose-escalation cohorts (appendix p 8).
Table 3:
Antitumour activity by disease type and subgroup
| Evaluable patients | Overall response | Complete response | |
|---|---|---|---|
|
| |||
| Follicular lymphoma | |||
| Overall | 62 | 51 (82%; 70–91) | 14 (23%; 13–35) |
| Zandelisib monotherapy | 41 | 32 (78%; 62–89) | 9 (22%;11–38) |
| Zandelisib plus rituximab | 21 | 19 (90%; 70–99) | 5 (24%; 8–47) |
| Refractory to rituximab* | 8 | 7 (88%; 47–100) | 1 (13%; 0–53) |
| Relapsed to rituximab* | 13 | 12 (92%; 64–99) | 4 (31%; 9–61) |
| Continuous dosing group (zandelisib monotherapy) | 25 | 19 (76%; 55–91) | 4 (16%; 4–36) |
| Intermittent dosing group | 37 | 32 (86%; 71–95) | 10 (27%; 14–44) |
| Zandelisib monotherapy | 18 | 14 (78%; 52–94) | 5 (28%; 10–53) |
| Zandelisib plus rituximab | 19 | 18 (95%; 74–100) | 5 (26%; 9–51) |
| Chronic lymphocytic leukaemia or small lymphocytic lymphoma | |||
| Overall | 20 | 20 (100%; 83–100) | 5 (25%; 9–49) |
| Zandelisib monotherapy | 13 | 13 (100%; 75–100) | 4 (31%; 9–61) |
| Zandelisib plus rituximab | 7 | 7 (100%; 59–100) | 1 (14%; 4–58) |
| Continuous dosing group (zandelisib monotherapy) | 10 | 10 (100%; 69–100) | 3 (30%; 8–65) |
| Intermittent dosing group | 10 | 10 (100%; 69–100) | 2 (20%; 3–57) |
| Zandelisib monotherapy | 4 | 4 (100%; 40–100) | 1 (25%; 6–81) |
| Zandelisib plus rituximab | 6 | 6 (100%; 54–100) | 1 (17%; 4–64) |
| Marginal zone lymphoma | |||
| Zandelisib plus rituximab† | 4 | 4 (100%; 40–100) | 1 (25%; 6–81) |
| Diffuse large B-cell lymphoma | |||
| Zandelisib plus rituximab† | 9 | 1 (11%; 3–48) | 1 (11%; 3–48) |
Data are n or n (%; 95% CI).
Post-hoc analysis.
All on intermittent dosing.
Duration of response and progression-free survival by tumour type and treatment regimen are shown in the appendix (pp 3–5).
Discussion
In this phase 1b dose-escalation study of zandelisib alone or in combination with rituximab in patients with relapsed or refractory B-cell malignancies, oral zandelisib administered on an intermittent dosing schedule of 60 mg once daily on days 1–28 of cycles 1–2 and days 1–7 of subsequent 28-day cycles was well tolerated, with low frequencies of grade 3 or worse adverse events and immune-related toxicities. Since immune-related toxicities have substantially limited the adoption of PI3Kδ inhibitors in clinical practice,11,12 we hypothesise that zandelisib has the potential to overcome the safety challenges of the PI3Kδ inhibitor class. Moreover, intermittent dosing did not result in reduced efficacy, as patients with follicular lymphoma, chronic lymphocytic leukaemia or small lymphocytic lymphoma, or marginal zone lymphoma had high overall response rates, both overall (82% with follicular lymphoma, 100% with chronic lymphocytic leukaemia or small lymphocytic lymphoma, and 100% with marginal zone lymphoma) and across different subgroups by treatment and by dosing schedule.
The initial dose of 60 mg showed a high overall response rate in patients with relapsed follicular lymphoma and relapsed chronic lymphocytic leukaemia, and was well tolerated, with no dose-limiting toxicities reported. Two additional dose levels were evaluated after a protocol amendment to further assess the safety and tolerability of zandelisib and establish the pharmacokinetic profile for several doses, and it was concluded that continued dose escalation solely to define the maximum tolerated dose was not needed. Because there was no apparent difference in the incidence and severity of adverse events across all of the three doses tested, with similar preliminary activity, the lowest dose of 60 mg was selected as the recommended phase 2 dose for further evaluation, both as monotherapy and in combination with rituximab. It is possible that continuous dosing with doses of less than 60 mg might further improve tolerability. However, pharmacokinetic modelling predicted that doses of less than 60 mg would result in plasma concentrations below the target needed to fully inhibit PI3Kδ in all patients.15 Given these pharmacokinetic modelling data, and that our intermittent dosing strategy resulted in a favourable safety profile compared with previous PI3Kδ inhibitors (despite a longer median duration of therapy in this study) without compromising efficacy, we did not evaluate lower doses.
As the initial cohorts of patients in the dose-escalation study received zandelisib using the daily continuous dosing schedule, we observed class-specific immune-related toxicities (eg, diarrhoea or colitis, rash). Upon amending the protocol to evaluate zandelisib using intermittent dosing, patients already on study were switched to intermittent dosing and subsequently enrolled patients received zandelisib on the intermittent dosing therapy schedule. The intermittent dosing strategy resulted in a lower cumulative risk of grade 3 or worse adverse events of special interest beyond cycle 3, with grade 3 or worse diarrhoea or colitis occurring in 8% of patients, grade 3 or worse rash occurring in 5%, and no grade 4 adverse events of special interest. With intermittent dosing, most of these adverse events of special interest occurred in the first 3 months of therapy, which included the initial two cycles of daily dosing and the following cycles, which suggests residual effects of continuous PI3Kδ inhibitor exposure. We also observed low rates of grade 3 or worse pneumonia (2%) and grade 3 or worse aminotransferase increase (5%). Aminotransferase elevation occurred early in two of the three patients and did not recur upon rechallenge in all cases. The discontinuation rate due to adverse events (about 10% with zandelisib) was lower than rates of approximately 20–40% reported with early-generation oral PI3Kδ inhibitors.21 Notably, the lower rate of grade 3 adverse events of special interest in the intermittent dosing group than in the continuous dosing group should be viewed in the context of longer treatment exposure with intermittent dosing (median treatment duration 15·2 months vs 10·4 months with continuous dosing), which was likely to be due to fewer discontinuations because of toxicity in the intermittent dosing group. It is possible that beginning intermittent dosing from cycle 1 might further improve tolerability, and this is appealing when combining zandelisib with another active therapy if there is potential overlapping toxicity. Zandelisib is being evaluated with intermittent dosing from cycle 1 in other regimens, such as with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in diffuse large B-cell lymphoma and with zanubrutinib (BTK inhibitor) in B-cell malignancies.22 However, it is possible that beginning the intermittent dosing schedule from cycle 1 could result in less tumour debulking and reduced efficacy, particularly when zandelisib is administered as monotherapy.
Our findings led to two ongoing global studies in patients with follicular lymphoma and marginal zone lymphoma: a phase 2 study evaluating zandelisib monotherapy after failure of at least two previous therapies (NCT03768505) and a phase 3 study of zandelisib plus rituximab versus chemoimmunotherapy after failure of previous immunochemotherapy (NCT04745832). Zandelisib is also an appealing agent to study in combination with other targeted agents. Correlative T-cell subset analyses are planned in the phase 2 study to characterise the effect of intermittent dosing on regulatory T-cell function in a larger population of patients with uniform treatment exposure.
This study has some limitations, such as the small sample size, particularly for patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma, marginal zone lymphoma, and high-grade B-cell lymphoma. This study did not randomly assign patients to the continuous dosing or intermittent dosing groups. Therefore, although baseline characteristics of the two groups appeared to be similar, differences in the treated patient populations might partially account for the observed difference in the rates of immune-mediated adverse events. However, 21 (55%) of 38 patients in the continuous dosing group switched to intermittent dosing after a median of seven cycles, so these data might have underestimated the risk of immune-mediated adverse events with continuous dosing. Patients in the intermittent dosing group also had a longer median treatment exposure compared with the continuous dosing group due to reduced toxicity, which might have further led to underestimation of the difference in rates of immune-mediated adverse events between the two dosing groups. Although the sample size was small, baseline demographic data suggested that this was a representative cohort including patients with high-risk disease based on traditional risk factors (eg, proportion of patients with high disease burden, POD24 failure, or refractory to rituximab) or high disease burden. Results of the ongoing phase 2 and phase 3 trials are necessary to confirm the favourable anti-lymphoma activity and safety profile of zandelisib with intermittent dosing.
Supplementary Material
Research in context.
Evidence before this study
Despite substantial improvement in the management of patients with indolent B-cell malignancies, these diseases still eventually relapse or become refractory to available treatments. Phosphatidylinositol 3-kinase p110δ (PI3Kδ) is a validated therapeutic target in indolent B-cell malignancies; however, class-related toxicities have impeded the broader use of PI3Kδ inhibitors. Attempts to improve the tolerability of PI3Kδ inhibitors by modifying their dose or dosing schedule have resulted in loss of disease control. We searched PubMed for studies published in English from Jan 1, 2010, to Dec 31, 2020, using the terms “B-cell malignancies”, “therapy”, “non-Hodgkin lymphoma”, “NHL”, “relapsed”, “refractory”, and “trial”, but not including cell therapies, to identify reports of PI3Kδ inhibitors used to treat relapsed or refractory non-Hodgkin lymphoma. The published literature indicated substantial interest in identifying PI3Kδ inhibitors with improved tolerability and maintained efficacy, to be given as monotherapy or in combination with other agents.
Added value of this study
This study shows that zandelisib, a next-generation oral target-specific PI3Kδ inhibitor with differentiated pharmacological properties that enable dosing on an optimised intermittent dosing schedule, given as monotherapy or in combination with rituximab, leads to a high rate of durable responses and has a favourable toxicity profile. Given its tolerability profile, zandelisib could be combined with other agents and evaluated as an oral targeted agent for patients with indolent non-Hodgkin lymphoma and chronic lymphocytic leukaemia who have relapsed or refractory disease after standard of care.
Implications of all the available evidence
This study supports the further development of zandelisib as monotherapy or in combination with rituximab or other agents for the treatment of patients with B-cell malignancies.
Acknowledgments
The study was funded by MEI Pharma. We thank the investigators, site staff, and patients and their families for their participation in the study. Editorial support was provided by Ingrid Koo (Inkstone Consulting, Lafayette, LA, USA) and funded by MEI Pharma. We thank the Lymphoma Research Foundation, who supported JDS through the Lymphoma Clinical Research Mentoring Program. ADZ is supported by the MSK Cancer Center Core Grant P30-5P30CA008748-55 (PI Craig Thompson) and the MSK SPORE in Lymphoma P50-5P50CA192937-05 (PI Andrew Zelenetz).
Footnotes
Declaration of interests
JMP reports consulting fees from Beigene, Gilead, AstraZeneca, Incyte, and Epizyme. JDS reports research funding from Adaptive Biotechnologies, Beigene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, and TG Therapeutics; and consulting fees from AbbVie, AstraZeneca, Beigene, Bristol Myers Squibb, Roche, TG Therapeutics, and Verastem. NR reports research funding from MEI Pharma and Bristol Myers Squibb; and honoraria from Celgene and Bristol Myers Squibb. DJ reports consulting fees from MEI Pharma. AS reports institutional research funding from MEI Pharma, Merck, Bayer, Roche, Novartis, Pfizer, ADC Therapeutics, and Eli Lilly; and consulting fees from Bayer, Eli Lilly, Roche, and Novartis. AI reports institutional research funding from MEI Pharma. JL-S is a former employee of MEI Pharma, where she was a Medical Director, member of the Data Safety Monitoring Board, received support for attending meetings or travel, and holds ownership interest. JL-S is currently employed at BioAtla. JL is an employee of and holds ownership interest in MEI Pharma. ADZ reports institutional research funding from MEI Pharma; consulting fees for participating on an advisory board during conduct of study to review toxicity and develop alternative dosing; institutional research funding from Bayer; consulting fees from Beigene, Genentech/Roche, Debiopharm, Ono Pharma, Oncopeptides, SecuraBio, and Quant Health; payment or honoraria for an internal presentation to Beigene; participation on a Data Safety Monitoring Board for Bristol Myers Squibb and Beigene; participation on an advisory board for MorphoSys, Kite/Gilead, Sandoz, AstraZeneca, Verastem, Coherus BioSciences, JUNO/Celgene/Bristol Myers Squibb, Beigene, and Karyopharm; and unpaid leadership roles for Lymphoma Research Foundation (Chair of Scientific Advisory Board and Board of Directors, through June, 2021). All other authors declare no competing interests.
Contributor Information
John M Pagel, Swedish Cancer Institute, Seattle, WA, USA.
Jacob D Soumerai, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Nishitha Reddy, Vanderbilt University Medical Center, Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
Deepa Jagadeesh, Cleveland Clinic, Cleveland, OH, USA.
Anastasios Stathis, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Universita della Svizzera Italiana, Lugano, Switzerland.
Adam Asch, Stephenson Cancer Center, Oklahoma City, OK, USA.
Huda Salman, Stony Brook University Hospital, Stony Brook, NY, USA.
Vaishalee P Kenkre, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
Alexia Iasonos, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Judith Llorin-Sangalang, MEI Pharma, San Diego, CA, USA.
Joanne Li, MEI Pharma, San Diego, CA, USA.
Andrew D Zelenetz, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Data sharing
Individual participant data that underlie the results reported in this Article, after deidentification (text, tables, figures, and appendices) will be shared. The study protocol, statistical analysis plan, and analytic code will be available upon request at completion of the trial to achieve aims in approved proposals. Proposals should be directed to rghalie@meipharma.com; to gain access, data requestors will need to sign a data access agreement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Individual participant data that underlie the results reported in this Article, after deidentification (text, tables, figures, and appendices) will be shared. The study protocol, statistical analysis plan, and analytic code will be available upon request at completion of the trial to achieve aims in approved proposals. Proposals should be directed to rghalie@meipharma.com; to gain access, data requestors will need to sign a data access agreement.