Feasibility pilot trial of a tailored medication adherence-promotion intervention for adolescents and young adults with cancer: Study design and protocol.

BACKGROUND: Medication non-adherence is common among adolescents and young adults (AYAs) with cancer and associated with poor health outcomes. AYAs with cancer endorse multiple barriers to adherence that differ across individuals, suggesting that tailoring intervention content to an AYA's specific barriers may have the potential to improve adherence. The purpose of this manuscript is to report on ORBIT-guided Phase I design efforts to create the first tailored adherence-promotion intervention for AYAs with cancer and the study protocol for the ongoing Phase II pilot feasibility trial. METHODS: Phase I design included qualitative interviews (n = 15 AYAs) to understand patient preferences for adherence-promotion care, development and refinement of a best-worst scaling exercise barriers tool (n = 5 AYAs), and development of intervention modules and a tailoring algorithm. In the ongoing Phase II pilot feasibility trial, AYAs (ages 15-24 years) with cancer currently taking oral chemotherapy or prophylactic medication will be recruited from three children's hospitals. Feasibility, acceptability, and usability will be assessed and these outcomes along with data on medication adherence will be used to inform the next phases of intervention development and testing. CONCLUSIONS: If promising, this program of research ultimately has the potential to equip clinicians with additional strategies for supporting adherence among AYAs with cancer. NCT05706610.

Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).

BACKGROUND: Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. PROCEDURE: The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. RESULTS: Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. CONCLUSIONS: Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50 mg/m2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

Brentuximab vedotin after autologous transplantation in pediatric patients with relapsed/refractory Hodgkin lymphoma.

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with ∼50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplantation (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with data of only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy after ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This is the largest cohort reported to date. We found that brentuximab vedotin was well tolerated with a safety profile similar to that of adult patients. With a median follow-up of 37 months, the 3-year PFS was 85%. These data suggest a potential role for the use of brentuximab vedotin as consolidation therapy after ASCT for children with relapsed/refractory HL.

The Choice of Either Conventional Chemotherapy or Inotuzumab Ozogamicin as Bridging Regimen Does Not Appear To Impact Clinical Response to CD19-Directed CAR-T Therapy in Pediatric B-ALL.

Bridging therapy (BT) given during the period between T-cell collection and initiation of lymphodepleting chemotherapy is indicated for most children with B-cell acute lymphoblastic leukemia (B-ALL) undergoing treatment with tisagenlecleucel (tisa-cel), a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. Both conventional chemotherapy agents and B-cell directed antibody-based therapies such as antibody-drug conjugates and bispecific T-cell engagers have been used as systemic forms of BT. The purpose of this retrospective study was to evaluate if there are detectable differences in clinical outcomes based on the type of BT given (conventional chemotherapy or inotuzumab). A retrospective analysis was performed on all patients treated with tisa-cel at Cincinnati Children's Hospital Medical Center for B-ALL with bone marrow disease (with or without extramedullary disease). Patients who did not receive systemic BT were excluded. Only 1 patient received blinatumomab as BT and was therefore not included in this analysis to focus the analysis on the use of inotuzumab. Pre-infusion characteristics and post-infusion outcomes were collected. Fisher's exact test was used for categorical variables, and t-test or Mann-Whitney test was used for continuous parametric and non-parametric variables respectively. Mantel-Cox was used for survival analyses. Thirty-two patients received BT before CD19 CAR-T for medullary leukemia; 24 received conventional chemotherapy, and 8 received inotuzumab ozogamicin (InO). Cohorts were evenly matched regarding CAR-T indication, recipient age, and median CAR-T cell dose. There were no significant differences between the groups for attaining a minimal residual disease (MRD)-negative complete response after CAR-T, the percentage of patients who maintained prolonged B-cell aplasia, or the median duration of B-cell aplasia. Thirty-seven percent of patients in the conventional chemotherapy group and 43% in the antibody-based therapy group relapsed, with a median time to relapse in both groups of 5 months. No differences in event-free survival, the cumulative incidence of relapse, or overall survival were seen between the two groups. Initial response to tisa-cel, relapse rate, and survival were similar between patients who received BT with conventional chemotherapy or InO therapy. Because low disease burden at the time of infusion is a positive prognostic factor, choice of bridging regimen should focus on therapy that is anticipated to effectively lower disease burden and minimize treatment-related toxicity. Given the limitations associated with the single center retrospective analysis, a larger, multicenter study is needed to further explore these findings.

Barriers to medication adherence among adolescents and young adults with cancer.

BACKGROUND: Adherence promotion is a critical component of adolescent and young adult (AYA) cancer care, but predictors of nonadherence that could be targeted in intervention efforts remain largely unknown. The purpose of this multi-site longitudinal observational study was to examine the relationship between barriers and medication adherence among AYAs with cancer. PROCEDURE: Sixty-five AYAs (ages 15-24 years; mean age = 18.97 years, SD = 2.51; Mmean time since diagnosis = 1.42 years, SD = 1.95) with newly diagnosed or relapsed cancer completed self-report measures of barriers and adherence at quarterly study visits and used an electronic adherence monitoring device for 12 months. Longitudinal mixed effects models were used to examine our primary hypothesis that greater barriers are related to lower adherence over time. Descriptive statistics were used to explore our secondary aim of describing the frequency and patterns of barriers endorsed by AYAs with cancer. RESULTS: After controlling for covariates (time, medication type, race, ethnicity, diagnosis, time since diagnosis), a greater number of barriers was associated with lower electronically monitored (ß = -5.99, p = .005) and self-reported (ß = -1.92, p < .001) adherence. The specific barriers endorsed by AYAs differed across participants, and the majority of AYAs endorsed an entirely different pattern of barriers than any other AYA in the study. CONCLUSION: Barriers are associated with nonadherence and may be a promising target for intervention. Individual variability across barriers, however, suggests that tailoring may be necessary, and a promising next step is to explore personalized approaches to adherence promotion.

Adherence and Barriers to Inpatient Physical Therapy Among Adolescents and Young Adults with Hematologic Malignancies.

This study described inpatient physical therapy (PT) adherence and barriers to inpatient PT among adolescents and young adults (AYAs) with hematologic malignancies receiving care at a Midwestern children's hospital. Forty-seven AYAs receiving care over a 2-year period were included. PT contact was established in 93% of hospitalizations. AYAs declined an average of 34% of PT visits, resulting in PT visits on 27% of hospitalized days, 1 day less than the goal of 3 days a week. The most frequent reasons for decline included: AYA sleeping (22%), AYA undergoing medical procedure (18%), and AYA not feeling well (12%).

Treatment of posttransplant lymphoproliferative disorder with poor prognostic features in children and young adults: Short-course EPOCH regimens are safe and effective.

No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.

Active and Protected: Developing a "Safer Sex" Handout for Adolescents and Young Adults with Cancer.

There is a critical need to engage adolescents and young adults (AYAs) with cancer in conversations regarding "safer" sexual activity during treatment. Many providers, however, report lacking the knowledge and/or tools to engage in these discussions. This article describes the experience of one pediatric institution in assessing and addressing provider barriers to safer sexual activity discussions among AYAs with cancer. Feedback from patients and providers resulted in an educational handout detailing recommendations regarding safer sex practices for AYAs with cancer. Handout adoption, acceptability, appropriateness, and feasibility are described alongside barriers to assist other institutions seeking to develop similar interventions.

Location of Death and End-of-Life Characteristics of Young Adults with Cancer Treated at a Pediatric Hospital.

Background: Location of death (LOD) is an important aspect of end-of-life (EOL) care. Adolescents and young adults (YAs) with pediatric malignancies are increasingly treated in pediatric institutions. YAs, generally defined as 18-39 years old, deserve specific attention because adults have unique developmental and social considerations compared with younger patients. Objective: The goal of this retrospective cohort study was to understand the effect of treatment by a pediatric oncology program on EOL experiences for YAs. Specifically, we examined LOD, hospice, and palliative care (PC) involvement in a cohort of YAs who died of cancer in a large, quaternary care pediatric hospital. Methods: This was a retrospective cohort study of patients ≥18 years of age, who died of cancer between January 1, 2010, and December 31, 2017. Standardized data were abstracted from the institutional cancer registry and the electronic medical record. Results: YAs in this cohort more commonly died in the hospital (54.9%). Lack of hospice involvement and the presence of a documented do-not-resuscitate (DNR) order were significantly associated with inpatient death. The majority of patients had long-standing PC involvement (95.8%, median 318 days), a DNR order (78.9%), and had enrolled in hospice care (60.6%) before death. Conclusions: These results suggest that a significant proportion of YAs with cancer remain inpatient for EOL care. Pediatric oncologists and PC teams may benefit from additional training in the unique psychosocial needs of YAs to optimize EOL care for these older patients.

Collaborating with Adolescents and Young Adults with Cancer as Advisors.

There is a growing interest by both pediatric and medical oncologists to develop adolescent and young adult (AYA)-specific cancer programs. Input from AYA patients is critical to the successful design of these programs and to ensuring that patient needs are met. As traditional in-person advisory groups may not be the most appropriate means for engaging AYAs, this article describes the creation and implementation of a novel, developmentally appropriate, and efficient Young Adult Advisory Program. Reach, uptake, and participant demographic and clinical characteristics are presented alongside lessons learned. The findings are offered to assist others seeking to engage AYAs in program development and quality improvement efforts.

Phase 1 trial of ontuxizumab (MORAb-004) in children with relapsed or refractory solid tumors: A report from the Children's Oncology Group Phase 1 Pilot Consortium (ADVL1213).

BACKGROUND: Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation. METHODS: Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation. RESULTS: Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg. CONCLUSION: Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults.

Evaluating the role of phase I expansion cohorts in oncologic drug development.

Importance Use of expansion cohorts (EC) in phase I trials is increasing. However, the utility of phase I EC in aiding drug development is unclear. We sought to determine factors associated with the inclusion of EC in phase I studies and the impact of EC on subsequent clinical development. Methods We performed a systematic review of all phase I trials published in the Journal of Clinical Oncology between June 2004 and May 2014. Presence of an EC, number of participants, funding source, class of agent, tumor type, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) were identified. Subsequent conduct of phase II studies and FDA approval of the study agent was also assessed. Results We identified 252 phase I studies. An EC was included in 105 studies. Average accrual on EC studies was 47 compared to 31 in studies without EC (p < 0.0001). There was no impact of time on the inclusion of EC. Only 4 % of phase I studies with an EC provided sample size justification. Source of funding had the only significant association with inclusion of EC. Addition of a phase I EC did not impact the phase I MTD/RP2D, subsequent phase II trial, or FDA approval. Conclusion The importance of including an EC in phase I trials is subject to ongoing debate. Our results demonstrated little benefit to including EC in phase I studies. These findings support that innovative design strategies are needed to optimize the utility of EC in phase I studies.

Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment.

AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.

A liquid chromatography/tandem mass spectrometry method for determination of obatoclax in human plasma.

We describe a selective and highly sensitive high-performance liquid chromatography-electrospray ionization-collision induced dissociation-tandem mass spectrometry (HPLC-ESI-CID-MS/MS) assay for the pan-antiapoptotic Bcl-2 family inhibitor, obatoclax, in human plasma. Fifty µL plasma specimens were prepared by addition of extraction solution consisting of Mobile Phase A (10mM ammonium formate (aq) titrated to pH of 3.0 with formic acid): Mobile Phase B (100% methanol) (20:80, v,v) and internal standard followed by centrifugation. HPLC separations were performed on a Waters, YMC-Pack™, ODS-AQ™ S-3 analytical column with LC mobile phase A and B. Linearity and sensitivity was assessed over a linear range of 0.04-25ng/ml at eleven concentrations. The lower limit of quantification for obatoclax was 0.04ng/mL. The intra-day precision based on the standard deviation of replicates of quality control (QC) samples ranged from 0.9 to 5.1% and the accuracy ranged from 98.9 to 106.8%. Stability studies performed replicate sets of QC samples (0.1ng/mL, 2.5ng/mL, and 15ng/mL) showed that obatoclax in human plasma was stable at room temperature for 24h as well as at -80°C for 1m and 2y. Stability was also demonstrated after 3 freeze/thaw cycles (RT to -80°C). The analytical method showed excellent sensitivity, precision, and accuracy. This method is robust and has been successfully employed in a Children's Oncology Group Phase 1 Consortium study of obatoclax in children with cancer.

Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors.

BACKGROUND: EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors. PROCEDURE: EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2) ). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination. RESULTS: Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2) . At dose levels above 16 mg/m(2) , Grade ≥3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2) . Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for ≥8 cycles. CONCLUSIONS: EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma.

Evaluation of the retinoids with cisplatin and vincristine in xenograft models of neuroblastoma.

Retinoids have been studied for the treatment of children with neuroblastoma for >25 years. Posttransplant administration of isotretinoin is standard of care for children with high-risk neuroblastoma, whereas fenretinide remains investigational. Previous preclinical studies have evaluated the interaction of retinoids and cytotoxic agents with conflicting results. We evaluated the schedule-dependent interaction of the cytotoxic agents, vincristine and cisplatin, with the retinoids, isotretinoin and fenretinide, in xenograft models of neuroblastoma. Concomitant administration of isotretinoin or fenretinide with the cytotoxic agents did not result in any clear potentiation of cytotoxicity.

Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) signals DNA damage and facilitates DNA repair. PARP inhibitors are being evaluated in cancers with defective DNA repair mechanisms or in combination with cytotoxic therapy or radiation. We evaluated the PARP inhibitor, olaparib, in combination with chemotherapy using in vitro and in vivo pediatric solid tumor models. PROCEDURE: The IC50 of olaparib alone and in combination with cytotoxic agents was determined in 10 pediatric solid tumor cell lines. Synergy was assessed using the combination index of Chou-Talalay. Olaparib alone and in combination with topotecan/cyclophosphamide was evaluated in xenograft models of Ewing sarcoma (RD-ES) and neuroblastoma (NGP). PAR activity was evaluated in cell lines and tumor lysates. RESULTS: Olaparib induced growth inhibition, median (range) IC50 = 3.6 (1-33.8) µM, and inhibited PAR activity in pediatric solid tumor cell lines. The addition of olaparib to DNA damaging agents resulted in additive to synergistic interactions. In RD-ES and NGP xenografts, olaparib inhibited PAR activity by 88-100% as a single agent and 100% when administered with cyclophosphamide/topotecan. Although the addition of olaparib did not antagonize the activity of cyclophosphamide/topotecan, clear evidence of synergy could not be demonstrated. CONCLUSIONS: In pediatric solid tumor cell lines, clinically achievable concentrations of single agent olaparib caused growth inhibition. Although the in vitro data demonstrated synergistic efficacy of olaparib when added to the camptothecins and alkylating agents, synergy was not discernible in vivo. Clinical trials of PARP inhibitors in combination DNA damaging agents are necessary to establish the role of PARP inhibitors in childhood cancer.

Challenges and opportunities in childhood cancer drug development.

Advances made in the treatment of childhood malignancies over the past four decades have resulted in overall 5-year survival rates of approximately 80%. However, despite these advances, several childhood cancers still have unacceptably low cure rates, and, even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. The development of molecularly targeted anticancer drugs offers the prospect of more effective therapy with fewer side effects, but will require increasing partnership between governments, and the academic and private sectors.