Clinical Updates, August 2018

BrainChild-01 Will Evaluate CAR T Cells in Pediatric CNS Tumors

Investigators at Seattle Children’s Hospital have initiated enrollment in the BrainChild-01 trial, which is designed to test chimeric antigen receptor (CAR) T-cell therapy in children and young adults with relapsed/refractory brain and central nervous system (CNS) tumors. Intriguingly, the modified CAR T cells will not be infused intravenously—rather, they will be injected either directly at the site of tumor resection or into the ventricular system of the CNS.¹

According to the National Brain Tumor Society, about 28,000 US children are living with a brain tumor, and 4610² cases of childhood and adolescent primary malignant and nonmalignant brain and CNS tumors are expected to be diagnosed in 2018. Brain tumors surpass leukemia as the leading cause of cancer-related deaths among children and adolescents.

Direct infusion of CAR T cells into the resected tumor cavity in the brain is also being evaluated in adult patients. Speaking at the recent annual meeting³ of the American Society of Clinical Oncology, Amy B. Heimberger, MD, a professor in the Department of Neurosurgery at The University of Texas MD Anderson Cancer Center, told the audience that the process helps overcome the lack of T-cell infiltration in the tumor. Multiple intracranial infusions of interleukin-13 receptor α2 CAR T cells in the resected tumor cavity of a patient with recurrent multifocal glioblastoma, as well as in the ventricular system, resulted in a regression of intracranial and spinal tumors in that patient. The response was sustained for 7.5 months.

The phase 1 BrainChild-01 study expects to recruit 26 patients with recurrent or refractory HER2-positive CNS tumors. The participants will be treated with autologous CD4 and CD8 T cells transduced to express a HER2-specific CAR and a truncated human epidermal growth factor receptor polypeptide, or EGFRt. Children with HER2-positive tumors that have relapsed or are refractory to prior treatment and who meet the trial’s inclusion criteria⁴ will undergo apheresis.⁵ The collected T cells will then be genetically modified to target HER2 gene-expressing tumor cells, and the modified cells will be administered through an indwelling catheter in 2 phases:

• A weekly dose for 3 weeks, followed by a week off and an examination period
• Weekly dose for 3 weeks

Following evaluation of treatment impact, including magnetic resonance imaging, patients can receive 6 more courses of infusion if there are T cells available and patients have not had adverse effects.

Primary outcomes that the study plans to measure include safety and feasibility of administering the CAR T-cell infusion directly into the tumor cavity.

Secondary objectives include examining the distribution of CAR T cells in the cerebrospinal fluid, their diffusion into the bloodstream, and, if possible, monitoring HER2 gene expression in the tumors at diagnosis versus at recurrence.

BrainChild-01, as the trial is named, will initially leave out patients diagnosed with diffuse intrinsic pontine gliomas, or DIPG tumors, highly aggressive tumors found at the base of the brain. However, Seattle Children’s Hospital plans to include children needing treatment for DIPG tumors in future BrainChild trials.

References

1. T-Cell immunotherapy for brain and central nervous system tumors. Seattle Children’s Hospital website. seattlechildrens.org/clinics-programs/cancer/research-and-clinical-trials/t-cell-therapy-brain-cns/. Published June 2018. Accessed July 5, 2018.
2. Quick brain tumor facts. National Brain Tumor Society website. braintumor.org/brain-tumor-information/brain-tumor-facts/. Accessed July 5, 2018.
3. Dangi-Garimella S. Identifying rational immunotherapy combinations for glioblastoma: a progress report. The American Journal of Managed Care^® website. ajmc.com/conferences/asco-2018/identifying-rational-immunotherapy-combinations-for-glioblastoma-a-progress-report?p=2. Published June 2, 2018. Accessed July 5, 2018.
4. HER2-Specific CAR T Cell Locoregional Immunotherapy for HER2-Positive Recurrent/Refractory Pediatric CNS Tumors. clinicaltrials.gov/ct2/show/NCT03500991?term=BrainChild-01&rank=1. Updated June 20, 2018. Accessed July 5, 2018.
5. Dangi-Garimella S. Q&A with Dr Jae Park on the promise of CAR-T cells in cancer care. The American Journal of Managed Care^® website. ajmc.com/journals/evidence-based-oncology/2017/february-2017/q-a-with-dr-jae-park-on-the-promise-of-car-t-cells-in-cancer-care/. Published February 16, 2017. Accessed July 5, 2018.

Research Highlights Long-Term Survival and Health-Related QoL in Patients With Newly Diagnosed MM

Research presented at the 2018 American Society of Clinical Oncology Annual Meeting identified predictors of long-term survival and health-related quality of life in patients with newly diagnosed multiple myeloma (MM).

The first abstract used data from the registry, a multicenter prospective observational cohort study in the United States designed to examine diagnostic and treatment patterns, clinical outcomes, and quality of life in patients with newly diagnosed MM, in order to identify characteristics associated with overall survival of 6 years or greater versus death at less than 6 years.¹

As of February 2017, the median follow-up was 65.4 months. Baseline characteristics associated with overall survival of 6 years or greater included age (being 70 years old or younger); Eastern Cooperative Oncology Group Performance Status of grade 0 or 1 (being fully active or being restricted in physically strenuous activity but ambulatory); lower International Staging System stage, which is used to prognosticate MM severity; and lack of history of diabetes.

In addition, the investigators found that patients who had an overall survival of 6 years or longer also had higher rates of triplet treatment, stem cell transplant, and maintenance therapy (with or without stem cell transplant), as well as higher response rates.

The second abstract focused on patients with newly diagnosed MM who are ineligible for stem cell transplantation (SCT) as part of ALCYONE, an ongoing multicenter, open-label, phase 3 trial.² Participants are not eligible for high-dose chemotherapy with SCT because of their age (65 years or older) or coexisting conditions. The trial has shown³ significant progression-free survival (PFS) with patients treated with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) compared with patients receiving bortezomib, melphalan, and prednisone alone (VMP).

“Measuring patient-reported outcomes (PROs) alongside disease progression provides the patient perspective on quality of survival and the value of health-related quality of life (HRQoL) for treatment decisions,” the authors of the abstract explained.

Patients completed the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) and the EuroQol Questionnaire at baseline and every 3 months during treatment. A total of 350 patients were receiving D-VMP, and 356 received VMP. The investigators found better HRQoL in patients in the D-VMP arm, plus 59.7% of patients receiving D-VMP reported meaningful improvement in global health status, as measured by EORTC QLQ-C30, compared with 52% of patients receiving VMP.

“Improvements in HRQoL were consistent with the clinical benefit showing superior PFS of D-VMP over VMP alone,” the authors concluded.

References

1. Gasparetto C, Rifkin RM, Terebelo HW, et al. Predictors of long-term survival in newly diagnosed multiple myeloma (NDMM) patients (pts) enrolled in the Connect MM Registry. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 8037. abstracts.asco.org/214/AbstView_214_214549.html.

2. Gries K, Fastenau J, Chen Y, et al. Health-related quality of life in patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation: results from the ALCYONE trial. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 8042. ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.8042.

3. Joszt L. Daratumumab approved as frontline treatment in newly diagnosed multiple myeloma. The American Journal of Managed Care^® website. ajmc.com/newsroom/daratumumab-approved-as-frontline-treatment-in-newly-diagnosed-multiple-myeloma. Published May 8, 2018. Accessed July 6, 2018.

Glasdegib Receives Priority Review Based on Results That Show Nearly Doubled OS in AML

Impressive phase 2 study results prompted the FDA to grant priority review designation to Glasdegib, an investigational oral smoothened inhibitor for treating adult patients with previously untreated acute myeloid leukemia (AML) in combination with low-dose chemotherapy (cytarabine).

Findings from the randomized phase 2 trial showed a 49.9% reduction in the risk of death for patients treated with glasdegib plus cytarabine compared with patients treated with cytarabine alone. The Prescription Drug User Fee Act goal date for the FDA’s decision is in December 2018.

“Patients with acute myeloid leukemia who are ineligible for intensive chemotherapy are in critical need of new treatment options to improve their overall survival,” Mace Rothenberg, MD, chief development officer of oncology at Pfizer Global Product Development, said in a statement.¹

In the phase 2 BRIGHT 1003 study, a randomized, open-label, multicenter trial, 88 patients received 100 mg daily of glasdegib with 20 mg of cytarabine twice daily, and 44 patients received cytarabine alone. The median overall survival (OS) was 8.8 months for patients treated with glasdegib, whereas the patients on cytarabine alone had a median OS of 4.9 months.

The phase 2 trial results were originally presented at the 58th American Society of Hematology Annual Meeting and Exposition. After the findings were reported, Jorge Cortes, MD, an investigator in the trial and deputy chair and professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, explained that glasdegib works by disrupting the Hedgehog pathway, which is thought to play a role in the development of multiple types of cancer.

“The Hedgehog pathway is a compelling target in cancer research because of the ability to target and disrupt the root of the cancer; that is, the cancer-originating cell,” Cortes said in a statement in December 2016.² “As the first smoothened inhibitor to demonstrate clinical benefit in patients with AML and high-risk MDS [myelodysplastic syndrome] who were ineligible for intensive chemotherapy, these results with glasdegib provide hope that interfering with this pathway may lead to potential new treatment options for blood cancers that may improve patient outcomes.”

The most common serious adverse effects were febrile neutropenia (29% of patients in the glasdegib arm vs 20% in the cytarabine alone arm) and pneumonia (21% vs 17%).

References

1. US FDA grants priority review for Pfizer’s new drug application for glasdegib in patients with previously untreated acute myeloid leukemia [press release]. New York, NY: Pfizer; June 27, 2018. press.pfizer.com/press-release/us-fda-grants-priority-review-pfizers-new-drug-application-glasdegib-patients-previous. Accessed July 9, 2018.
2. New phase 2 results show investigational compound glasdegib improved overall survival in acute myeloid leukemia and high-risk myelodysplastic syndrome [press release]. New York, NY: Pfizer; December 3, 2016. pfizer.com/news/press-release/press-release-detail/new_phase_2_results_show_investigational_compound_glasdegib_improved_overall_survival_in_acute_myeloid_leukemia_and_high_risk_myelodysplastic_syndrome. Accessed July 9, 2018.

PTAB Denis Samsung Bioepis' Request for IPR on Herceptin Patent

The United States Patent Trial and Appeal Board (PTAB) has denied biosimilar developer Samsung Bioepis’ request for inter partes review (IPR) of a patent that Genentech holds covering reference trastuzumab (Herceptin).¹

This is not the first time that the board has denied a claim for review of US patent 7,846,441. Previously, Hospira, owned by Pfizer, and Celltrion petitioned PTAB to review the Genentech patent in January 2017. The PTAB initially denied that request but reversed the decision after finding that Hospira had shown that each of the patent’s claims were likely invalid.

Celltrion filed its own challenge in March 2017, in which the PTAB had instituted an IPR, and Hospira subsequently joined.

Samsung Bioepis had stated that Genentech’s claim was obvious, based in part on a research paper, which also was cited in both prior claims from Celltiron and Hospira.

In the board’s denial of Samsung Bioepis’ request for an IPR proceeding, it explained that the company’s evidence brought nothing new to the table. The previously cited research paper was cited in an additional reference provided by Samsung Bioepis, and that reference was cited by yet another. “In other words, Bioepis’ arguments on the newly asserted references are substantially the same as those in the earlier cases,” said the board.

According to Genentech, that particular paper was also considered in the prosecution of the patent. “Thus, after considering the totality of the circumstances, we agree with [Genentech] that it is appropriate for us to exercise our discretion to deny the petition under 35 USC § 325(d),” the board stated.

Although the outcome favored Genentech, the pharma company is taking steps to further protect its drug from competitors and recently indicated plans² to seek injunctions to stop Samsung Bioepis from selling its biosimilar trastuzumab in Europe.

Genentech has requested US District Judge Robert Sweet to order Samsung Bioepis’ counsel, White & Case LLP, to share parts of its abbreviated biologics license application to examine certain chemical properties of the proposed trastuzumab biosimilar.

According to White & Case, Genentech is not entitled to receive this information from the European Medicines Agency and is “fishing” for grounds to challenge the biosimilar. The judge has yet to rule.

References

1. Bultman M. PTAB rejects Samsung challenge to Herceptin patent. Law 360 website. law360.com/lifesciences/articles/1054712/ptab-rejects-samsung-challenge-to-herceptin-patent?nl_pk=5d0ac488-f0bb-4d08-9a99-0117196d0e19&utm_source=newsletter&utm_medium=email&utm_campaign=lifesciences. Published June 18, 2018. Accessed June 19, 2018.
2. Newsham J. Genentech wants White & Case to share Samsung drug info. Law 360 website. law360.com/articles/1051153/genentech-wants-white-case-to-share-samsung-drug-info. Published June 6, 2018. Accessed June 19, 2018.

Progress Continues for Celltrion on Trastuzumab and Subcutaneous Infliximab Biosimilars

After receiving complete response letters (CRLs) in April 2018 for 2 proposed biosimilars,¹ Korean drug maker Celltrion announced² that it resubmitted its biologics license application (BLA) for CT-P6, a trastuzumab molecule referencing Herceptin. In May, the company resubmitted its BLA for CT-P10, a rituximab biosimilar referencing Rituxan.

According to a statement on Celltrion’s website, the FDA requested supplementary information about both products when it issued the CRLs, and the company worked closely with regulators to address issues identified in a February 2018 FDA warning letter related to manufacturing processes. It its announcement about trastuzumab’s resubmission, Celltrion indicated that the FDA had notified the company of its reinspection schedule, and both molecules could potentially be approved by the end of 2018.

Separately, Celltrion announced new data for its proposed subcutaneous formulation of its flagship biosimilar, CT-P13 (sold in the United States as Inflectra and in the European Union as Remsima). During the European League Against Rheumatism’s Annual European Congress of Rheumatology, held in June in Amsterdam, the Netherlands, investigators reported that the company’s subcutaneous CT-P13, which can be self-administered, had similar efficacy and generally similar safety to the currently approved intravenous (IV) CT-P13 up to week 30 in patients with rheumatoid arthritis (RA).³

In a study of 48 patients with RA, who were assigned to receive either IV infliximab or subcutaneous injections of 90, 120, or 180 mg of infliximab, disease improvement (assessed in terms of disease activity score in a count of 28 joints and the American College of Rheumatology’s criteria for 20% improvement) was comparable across all 4 treatment groups.

Two patients experienced hypersensitivity reactions, 1 of whom tested positive for antidrug antibodies at week 6.

Earlier this month, Celltrion reported positive results from a phase 1 study of its subcutaneous formulation of the biosimilar in patients with Crohn disease.⁴ In that study, patients who received IV therapy and those who received subcutaneous doses of 120, 180, and 240 mg showed similar improvement in terms of Crohn Disease Activity Index score.

Currently, patients with inflammatory diseases have no subcutaneous infliximab options; a self-administered option, if eventually approved, could offer greater flexibility in their treatment plans.

References

1. Davio K. FDA rejects Celltrion’s rituximab and trastuzumab biosimilars. The Center for Biosimilars website. centerforbiosimilars.com/news/fda-rejects-celltrions-rituximab-and-trastuzumab-biosimilars. Published April 5, 2018. Accessed June 18, 2018.
2. Celltiron completes resubmission to FDA for proposed trastuzumab biosimilar [press release]. Incheon, South Korea: Celltrion; June 18, 2018. businesswire.com/news/home/20180617005036/en/Celltrion-Completes-Resubmission-FDA-Proposed-Trastuzumab-Biosimilar. Accessed June 18, 2018.
3. Westhovens R, Yoo DH, Jaworski J, et al. Novel formulation of CT-P13 for subcutaneous administration in patients with rheumatoid arthritis: initial results from a phase i/iii randomised controlled trial. Presented at: the European League Against Rheumatism’s Annual European Congress of Rheumatology; June 13-16, 2018; Amsterdam, the Netherlands. Abstract THU0191.
4. Davio K. Celltrion reports positive phase 1 results for subcutaneous inflectra in CD. The Center for Biosimilars website. centerforbiosimilars.com/news/celltrion-reports-positive-phase-1-results-for-subcutaneous-inflectra-in-cd. Published June 5, 2018. Accessed June 18, 2018.

Download PDF: Clinical Updates