A Randomized Phase 2 Trial of Azacitidine ± Durvalumab as First-line Therapy for Higher-Risk Myelodysplastic Syndromes

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase inhibitory immune checkpoint (ICP) molecule expression. We conducted the first randomized phase 2 study of azacitidine plus the ICP inhibitor durvalumab versus azacitidine monotherapy as first-line treatment of higher-risk myelodysplastic syndromes (HR-MDS). Patients (N=84) received azacitidine 75 mg/m2 subcutaneously (days 1-7) with (Arm A) or without (Arm B) durvalumab 1500 mg intravenously on day 1 every 4 weeks. After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arms A and B received a median of 7.9 and 7.0 treatment cycles, respectively, with 73.7% and 65.9% completing ≥4 cycles. The overall response rate (primary endpoint) was 61.9% in Arm A (26/42) and 47.6% in Arm B (20/42; P=0.18), and median overall survival was 11.6 months (95% CI: 9.5, nonevaluable) versus 16.7 months (95% CI: 9.8, 23.5) (P=0.74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (A) and 81% (B). Grade 3 or 4 hematologic AEs were reported in (Arm A vs B) 89.5% vs 68.3% of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased PD-L1 (CD274) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining durvalumab and azacitidine in patients with HR-MDS was feasible, but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. ClinicalTrials.gov: NCT02775903

Randomized Study of Digital Life Coaching during Autologous Stem Cell Transplantation

BACKGROUND: Autologous stem cell transplantation (ASCT) for multiple myeloma (MM) entails sudden life changes including acute symptom burden, changes in physical function, and shifting caregiver dynamics. Several studies have shown that anxiety, insomnia, and distress rise in the initial weeks following ASCT before slowly recovering. Long-term consequences of these acute exacerbations include persistent quality of life (QOL) impairments (El-Jawahri 2016), post-traumatic stress disorder (Griffith 2020), and the usage of potentially inappropriate medications (PIMs) for symptom management (Banerjee 2021). We have recently completed a pilot study of digital life coaching (DLC), whereby life coaches work with patients via phone calls and text messages to provide longitudinal support, education, and accountability to meet wellbeing-related goals. Our pilot study of 15 patients demonstrated the feasibility of DLC during this period, with bidirectional patient-coach engagement occurring every 5-7 days even during index hospitalizations for ASCT (Banerjee 2021). Based on these positive results, we have now launched a randomized Phase 2 study of DLC versus usual care among patients with MM undergoing ASCT. STUDY DESIGN: Our study is registered at clinicaltrials.gov as NCT04589286. We plan to enroll 60 adult patients with MM undergoing first ASCT at our institution. Inclusion criteria include English language proficiency and ownership of a personal cellphone. However, neither smartphones nor specific mobile apps are required for study participation. All patients, including those in the control arm, receive brief wellness-related tips with each request for PRO data as outlined below. As shown in the Figure, patients in the DLC arm are paired with a trained life coach beginning at Day -10 before ASCT. Coaches use structured frameworks to assist patients longitudinally with identifying and accomplishing wellbeing-related goals. Specific coaching topics can vary from week to week and are set by each patient. In addition to weekly coach-led phone calls, patients are encouraged to maintain bidirectional communication via phone/text/email as often as desired. Patients in the control arm do not receive access to DLC. Our primary endpoint is the total usage of sedative-class PIMs - including lorazepam, temazepam, zolpidem, and other similar medications - prescribed for anxiety or insomnia during each of 4 four-week study subperiods identified in the Figure. Secondary endpoints include patient-reported outcome (PRO) assessments of QOL (PROMIS Global Health), distress (NCCN Distress Thermometer), and insomnia (PROMIS Sleep Disturbances 4A). PRO assessments are collected exclusively using automated REDCap emails every 1-2 weeks as shown in the Figure. PROGRESS TO DATE: As of the data cutoff (7/31/21), 19 patients have enrolled onto our study and 5 have completed all follow-up. The median age of enrolled patients is 62 (range: 31-77), with 26% of patients aged 70 or older. As shown in our pilot study (Banerjee 2021), PRO collection via automated REDCap emails is feasible. Specifically, of 93 email-based requests for PRO assessments as of the data cutoff, 92 (99%) have been completed. Analyses of PRO assessment responses and PIM usage will be conducted after study completion. DISCUSSION: Improving patient wellbeing during the acute peri-ASCT period is an unmet need in multiple myeloma. Published supportive strategies during this time include music therapy (Bates 2017), acupuncture (Deng 2018), palliative care (El-Jawahri 2017), and programmed hospital room lighting (Valdimarsdottir 2018). DLC may offer unique advantages given its easy accessibility and unified patient-facing interface across hospital/clinic/home transitions. These strengths may be particularly relevant in light of the COVID-19 pandemic, where home-based follow-up after ASCT has become more common. That being said, broadening the accessibility of DLC to include patients with limited English proficiency or patients without personal cell phones are important priorities for future studies. In summary, our randomized Phase 2 study of DLC versus usual care is ongoing. If shown to reduce PIM prescription rates while improving wellbeing-related PRO trajectories longitudinally, DLC may become a standard of care for patients with hematologic malignancies undergoing ASCT. Figure 1 Figure 1. Disclosures Banerjee: Pack Health: Research Funding; SparkCures: Consultancy; Sanofi: Consultancy. Knoche: Amgen: Honoraria. Brassil: Abbvie: Research Funding; Astellas: Research Funding; BMS: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; GSK: Research Funding; Sanofi: Research Funding; Pack Health: Current Employment. Jackson: Pack Health: Current Employment. Patel: Pack Health: Current Employment. Lo: Oncopeptides: Consultancy; EUSA Pharma: Consultancy. Chung: Caelum: Research Funding. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Wolf: Adaptive Biotechnologies: Consultancy; Teneobio: Consultancy; Sanofi: Consultancy; Amgen: Consultancy. Martin: Oncopeptides: Consultancy; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy. Shah: Bluebird Bio: Research Funding; GSK: Consultancy; Janssen: Research Funding; Indapta Therapeutics: Consultancy; BMS/Celgene: Research Funding; CareDx: Consultancy; CSL Behring: Consultancy; Kite: Consultancy; Nektar: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding.

Magnetismm-3: An Open-Label, Multicenter, Non-Randomized Phase 2 Study of Elranatamab (PF-06863135) in Patients with Relapsed or Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing. Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab. Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. Disclosures Lesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

CTNI-17. A PHASE 1 WITH DOSE EXPANSION/PHASE 2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA

BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D & E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.