How Do You Know if Your Tumor Is the Protein Cd 47

INTRODUCTION

Section:

CD47 was commencement identified every bit an integrin-associated transmembrane poly peptide that is ubiquitously found in normal and malignant tissues.ⁱ About cancer cells overexpress CD47, and the degree of expression independently correlates with poor clinical outcome in a variety of hematologic and solid tumor malignancies.^2,three The bounden of CD47 to its receptor signal receptor protein-α (SIRPα) on macrophages and dendritic cells results in an inhibition of phagocytosis. Thus, CD47 provides a potent "do not eat me" signal that allows for tumor cell evasion of allowed destruction by first-responder phagocytic cells and functions equally a dominant macrophage checkpoint.^3-v Blockade of CD47-SIRPα signaling in isolation is insufficient to trigger macrophage phagocytosis. Instead, additional prophagocytic signals are required, such as calreticulin and phosphatidylserine, which are frequently found on cancer cells.^6,7 CD47 also is widely expressed on normal tissues, but because normal cells lack prophagocytic signals, they are not susceptible to CD47-mediated phagocytosis. A notable exception is aging RBCs.⁸ Agents that inhibit CD47-SIRPα signaling tin induce macrophage phagocytosis of cancer cells both in vitro and in vivo, which results in growth inhibition and regression of a broad range of human cancer xenografts.^3,iv Therefore, the targeting of CD47 is a novel immunotherapeutic strategy for treating human cancers.

Hu5F9-G4 (5F9) is a humanized IgG4 monoclonal antibody with loftier analogousness for human CD47.^ix 5F9-mediated blockade of CD47 enhances the phagocytosis of cancer cells past macrophages. In preclinical in vivo models, 5F9 was active against a wide range of solid tumors, including cancers of the breast, ovary, colon, liver, brain, and other organs.^3-v Potent antitumor action also was observed in hematologic malignancies, including acute myeloid leukemia (AML), non-Hodgkin lymphoma, cutaneous T-cell lymphoma, astute lymphoblastic leukemia, and multiple myeloma.⁹ In human tumor xenograft models, 5F9 inhibited tumor prison cell growth and induced remission in established tumors.⁹ In preclinical toxicology studies, the major dose-limiting toxicity (DLT) was an on-target anemia¹⁰ that was mitigated past using a priming and maintenance dose schedule. Using this approach, nonhuman primates tolerated 5F9 doses up to 300 mg/kg without reaching a maximum tolerated dose (MTD).^ix

This report describes the first-in-man phase I trial of 5F9 in patients with advanced solid tumors and lymphomas. The trial consisted of iii singled-out dose escalation parts. Part A used weekly dosing to determine a tolerable twenty-four hours 1 priming dose. Function B administered the 5F9 priming dose identified in part A followed by escalation of weekly maintenance doses to establish an MTD. At the completion of part B, a tumor biopsy expansion cohort was opened. In part C, a loading dose was given on day 11 in addition to weekly 5F9 therapy to enable more-rapid attainment of therapeutic concentrations. The safety, tolerability, and early on efficacy results forth with summary pharmacokinetics (PK) and pharmacodynamics (PD) information are described hither. Detailed PK and PD findings will be reported elsewhere.

PATIENTS AND METHODS

Section:

Patient Selection and Oversight

Eligible patients were adults eighteen years of age or older with histologically or cytologically confirmed advanced solid malignancy or lymphoma previously treated with at to the lowest degree one regimen of systemic therapy, or who refused other systemic therapy, with an Eastern Cooperative Oncology Group operation status of 0 to two and for whom no curative therapy was available. Boosted eligibility criteria are outlined in the Information Supplement.

This study was approved by the human investigations committee at each institution, and in accordance with assurances filed with and approved by the Department of Health and Homo Services. These data are anonymized to protect the identities of the research participants. Informed written consent was obtained from each participant. Patients were enrolled from August 2014 through January 2018.

Study Design and Drug Administration

The principal objectives were to assess the safe and tolerability of 5F9 and to make up one's mind the recommended doses and schedules for additional trials. The secondary objectives were to evaluate the PK and PD profiles and to certificate antitumor activity. Handling cycles were 28 days long and connected until disease progression. In office A, the 5F9 starting dose of 0.1 mg/kg was infused intravenously weekly, with dose escalation conducted in single-patient cohorts for doses less than 3 mg/kg in a modified accelerated titration pattern.^xi The duration of the infusion was 1 hour for doses from 0.1 to one mg/kg and 2 hours for 3 mg/kg. In part B and beyond, all patients received a 1 mg/kg priming dose on day 1 for 3 hours followed by escalating maintenance doses for 2 hours on mean solar day 8 that began at the 3 mg/kg weekly dose level. After a safe dose was determined in part B, a solid tumor expansion cohort of 15 patients was opened, which required mandatory pretreatment and during handling tumor biopsies.

Beginning in office B, routine premedication with acetaminophen and an antihistamine was administered before the get-go two doses of 5F9. In role C, patients received a loading dose on solar day 11 of cycle i (cohorts of twenty, 30, and 45 mg/kg) in add-on to weekly maintenance dosing at the same level. Afterward cycle one, if patients had treatment delays longer than 4 weeks, repriming was required.

In part B, dose escalation was performed using a traditional 3 + 3 phase I study design.¹² DLT was defined equally any drug-related adverse event (AE) of class iii or greater that occurred from the time of outset dose in part A, or from the starting time maintenance doses in parts B and C, until the completion of 28 days of therapy (cycle ane), with exceptions that are listed in the Appendix. If a DLT was observed, the number of patients at that dose level was expanded from three up to 6. Form 3 anemia was excluded as a DLT considering it was expected and anticipated to be transient and reversible. The MTD was divers as the highest dose level explored that induced DLTs in less than 33% of patients. Upwardly to 10 more patients could be entered to any rubber dose level to collect boosted safety and PK data.

Written report Assessments

All patients who received at to the lowest degree 1 5F9 treatment were evaluated for safety. Standard safe assessments were conducted at baseline, before each weekly infusion, and out to 28 days after the last dose of report drug. Because of the possibility of hemagglutination, peripheral claret smear, visual acuity, and retinal photographic examinations were performed three times weekly for the first two weeks in function A. In part B, peripheral claret smears were examined on days ane, 2, viii, 9, 15, 22, and 29, and visual acuity was measured on days 1 and 8. However, there were no agin findings on retinal photography as assessed past an ophthalmologist in part A. Therefore, retinal photography was non performed in parts B and C. Routine laboratory assessments are detailed in the Appendix. AEs were graded according to the National Cancer Found Common Terminology Criteria for Adverse Events (version iv.03). Tumor measurements were obtained at baseline and every eight weeks until disease progression or study withdrawal. Response was determined using Response Evaluation Criteria in Solid Tumors (RECIST) version ane.1^thirteen or the International Working Group response criteria for malignant lymphomas.¹⁴ Details on PK and antidrug antibody (ADA) monitoring every bit well as PD receptor occupancy studies and tumor biopsy analyses are provided in the Data Supplement.

Statistical Analysis

This was an open-label, nonrandomized, offset-in-human dose escalation phase I trial. All patients exposed to 5F9 were included in the safety analysis, and all patients who had at least ane postbaseline tumor assessment were considered evaluable for tumor response assessment.

RESULTS

Department:

Patient Characteristics

The characteristics of all 62 treated patients are listed in Table ane. Female patients comprised 65% of participants and included xiii with ovarian cancer and five with chest cancer. The most frequent tumor type was colorectal cancer. Nine patients had salivary gland or caput and neck cancers, and ii had diffuse large B-jail cell lymphoma (DLBCL). Patients were heavily pretreated, having received a median of five systemic treatments (range, ane to 18 treatments) before study enrollment. The Eastern Cooperative Oncology Group operation status was 0 in 19 patients (thirty%), i in 42 patients (68%), and 2 in i patient (2%).

Tabular array one. Patient Demographics and Baseline Characteristics

Safety

The treatment cohorts and DLTs are listed in Table 2. Two DLTs were observed in part A at 3 mg/kg, including one patient who developed grade 3 right-side upper-abdominal hurting during the showtime infusion of 5F9 and ane patient with grade three hemagglutination defined every bit grade 2 headache associated with hemagglutination on the peripheral blood smear. Nevertheless, no DLTs were observed in the 6 patients treated at one mg/kg, so this dose was selected as the day 1 priming dose for employ in all subsequent parts of the report.

TABLE 2. Treatment Cohorts and DLTs

In role B, weekly maintenance doses were administered at iii, 10, and 20 mg/kg beginning on twenty-four hours eight after the priming dose. I patient at iii mg/kg had transient grade iii elevated bilirubin without changes in serum transaminases, which at the time was defined as a DLT. A second patient treated at twenty mg/kg had form 3 hemagglutination (grade 2 headache with hemagglutination on peripheral blood smear), but no other DLTs occurred in the vi patients treated at this dose level. Xv additional patients were treated with 20 mg/kg in the tumor biopsy expansion accomplice to collect additional PD data, and no DLTs were observed. In part C, one patient at 20 mg/kg experienced grade 3 elevated bilirubin, merely no additional DLTs occurred despite escalation to thirty mg/kg and 45 mg/kg in 9 and six patients, respectively. Thus, no MTD was reached in parts B or C. On the basis of this favorable safety contour and the accumulated PK data that demonstrated steady-country dose levels well above the targeted threshold of 200 μg/mL^fifteen (Fig 1A ), a maintenance dose of 30 mg/kg was recommended for additional clinical evaluation.

FIG 1. Hu5F9-G4 (5F9) pharmacokinetics and furnishings on hemoglobin and reticulocyte levels. (A) Concentration of 5F9 (mean ± standard difference) versus time during week 5 over the evaluated weekly dose range (1 to 45 mg/kg; number of patients per dose range, three to 30). (B) Anemia with compensatory reticulocytosis in one patient.

The combined AE profile from 44 patients treated with 5F9 maintenance doses of 20, thirty, and 45 mg/kg are listed in Table 3. Overall, the most mutual 5F9 toxicity was the expected on-target anemia, which occurred in 57% of patients treated with doses that ranged from twenty to 45 mg/kg (13% of patients with grade 3). Typically, a modest, predictable fall in hemoglobin (1 to 2 g/dL) occurred after the 1 mg/kg priming dose followed past a rapid compensatory reticulocytosis, as illustrated in a single patient in Effigy 1B . 5F9 handling was not associated with thrombocytopenia. In the 52 patients treated for at least iv weeks, the median percentage change in platelet count from baseline on solar day 29 at the end of the kickoff wheel was −3.ii% (range, −54.3% to 91.ii%). Five patients received concomitant anticoagulant therapy, merely no associated bleeding or thrombocytopenia was observed.

Tabular array 3. Adverse Upshot Summary for Patients Treated With Maintenances Doses of 20 mg/kg or Higher

Hemagglutination on the peripheral blood smear was noted in 36% of patients but was not associated with meaning clinical toxicities (2% grade 3). Specifically, no neurologic, renal, or cutaneous abnormalities were noted.

Other mutual toxicities were grade 1 and 2 fatigue (64%), headaches (50%; 2% grade iii), fever (45%), chills (45%), hyperbilirubinemia (34%), and arthralgias (18%). Unconjugated hyperbilirubinemia that was not associated with other liver office test abnormalities was mutual afterward the 5F9 priming dose; yet, it generally returned to baseline within a few days. Transient summit in unconjugated bilirubin was likely due to the expected phagocytosis of aged RBCs that effect from occludent of CD47. Equally such, in part B, the protocol was amended to exclude grade 3 hyperbilirubinemia from the DLT definition. Start- or 2nd-dose infusion-related reactions (IRRs) occurred in 34% of patients, predominantly in those enrolled in the 20 mg/kg and college dose cohorts. These were characterized past symptoms such as chills, fever/pyrexia, photopsia, back pain, and headaches that generally lasted a day or two after the associated infusion and were managed with symptomatic supportive care. Overall, but one patient underwent dose reduction from thirty to 20 mg/kg in part C because of an IRR, and this patient was able to receive further treatment without problems. One additional patient withdrew consent because of infusion-related AEs. Nevertheless, all other patients who experienced IRRs were able to keep treatment at their assigned dose level.

Transient grade three IRRs that responded to symptomatic treatment and that did non require dose reductions were non considered DLTs. No risk factors for IRRs were identified. After the first three patients were treated in the office C loading dose cohort at 30 mg/kg, routine antihistamine and acetaminophen premedication was mandated for all new patients before the initial priming dose of 1 mg/kg on solar day 1 and before the second college dose on 24-hour interval 8. Even so, fifty-fifty with routine prophylaxis, grade one or 2 IRRs that were managed symptomatically were mutual and reported in seven of 12 premedicated patients treated in role C at 30 or 45 mg/kg. Lymphopenia was found in 36% of patients without apparent clinical consequences. No handling-related deaths occurred on study.

Hemagglutination was seen on peripheral blood smear typically subsequently the kickoff or second 5F9 dose. However, at that place were no clear clinical sequelae. Specifically, no treatment-related peripheral vascular symptoms, changes in renal function, deep venous thromboses, pulmonary emboli, or other thrombotic events were observed. Furthermore, serial retinal photographs were collected over vii fourth dimension points in the first cycle to assess for microvascular changes, but no such findings were noted, then the protocol was amended to remove retinal photography evaluation in function B.

PK and ADA Assay

Similar to the PK in nonhuman primates, 5F9 exhibited nonlinear PK beliefs as a consequence of the CD47 antigen sink, which resulted in a curt credible half-life at doses of 0.1 to 3 mg/kg of 5F9 (Fig 1A ; and online but Appendix Tabular array A1). However, doses of x mg/kg and college saturated this sink, which extended the 5F9 half-life to approximately 13 days, consistent with other humanized monoclonal antibodies.¹⁶ At these doses, free antibody levels exceeded the antitumor activeness threshold of 200 μg/mL identified from PK modeling.^ix,15,19 Serum samples from six (ix.seven%) of 62 patients tested positive for ADA, only there was no impact on 5F9 PK and no apparent clinical symptoms.^xv Detailed PK profiling will exist presented elsewhere.

PD and Tissue Biopsy Analysis

Studies of RBC occupancy showed complete saturation of CD47 on RBCs at doses of 1 mg/kg and higher (Fig 2A ), which also supported 1 mg/kg as the initial 5F9 priming dose. In contrast, maximal saturation of CD47 on WBCs was merely observed after higher maintenance doses (Fig 2B ). Doses of 30 mg/kg maximally saturated CD47 on circulating WBCs.

FIG 2. Pharmacodynamics of Hu5F9-G4. (A) RBC receptor occupancy. (B) WBC receptor occupancy. (C) IgG4 immunohistochemical staining in a lymph node with tumor involvement obtained from a 70-twelvemonth-old patient with ovarian cancer treated with xxx mg/kg of 5F9. She remained on study for vii months with a best overall response of stable disease. 1/3 is 1 mg/kg priming dose and 3 mg/kg weekly dosing. one/10 is 1 mg/kg priming dose and 10 mg/kg weekly dosing. 1/xx is 1 mg/kg priming dose and twenty mg/kg weekly dosing. Po, mail-infusion sample collection; Pr, pre-infusion sample collection.

In addition, anti-IgG4 staining demonstrated strong antibody penetration into metastatic tumor tissue in an axillary lymph node from a patient with metastatic ovarian cancer (Fig 2C ). This patient was treated with 30 mg/kg 5F9, and the biopsy sample was obtained after 5 weeks of treatment. These nerveless data support the recommended dose of 30 mg/kg for phase Two evaluation.

Antitumor Activity

2 patients with articulate cell ovarian and fallopian tube carcinomas had confirmed fractional responses by RECIST version one.1 (Figs 3A and 3B ), with time to progression of 5.2 months and nine.2 months, respectively. These patients had reductions in target lesions of l% and 44%. Their cancer antigen 125 tumor markers dropped from 338 to lxx U/mL and 890 to 103 U/mL, respectively. Both patients were heavily pretreated with more than 6 prior lines of systemic therapy, and both received 5F9 at 20 mg/kg. A third patient with DLBCL at the twenty mg/kg maintenance dose had a mixed response by International Working Group criteria. This heavily pretreated patient with non-Hodgkin lymphoma had bulky lesions in the chest that decreased in size but had a solitary inguinal lymph node that increased while on treatment.

FIG iii. Hu5F9-G4 fractional responses observed in (A) a patient with clear cell ovarian cancer and (B) a patient with fallopian tube cancer.

Give-and-take

Section:

The anti-CD47 antibody 5F9 is well-tolerated in patients with solid tumors and lymphoma when administered using a priming and maintenance dose regimen. An MTD was non divers, even at doses up to 45 mg/kg weekly. The recommended 5F9 priming dose of 1 mg/kg on solar day ane achieved maximal CD47 receptor occupancy on RBCs. Receptor occupancy on circulating WBCs was not available at depression maintenance doses, just bachelor data confirmed consummate WBC receptor occupancy at weekly maintenance dosing of 30 mg/kg outset on day 8. A tissue biopsy sample of a lymph node with metastatic ovarian cancer in one patient demonstrated excellent penetration of 5F9 into the tumor microenvironment. At doses above ten mg/kg, the PK of 5F9 was linear, and increases in drug exposure were dose proportional. The resulting long terminal half-life of approximately 13 days supports every 2-calendar week dosing afterward saturating concentrations are achieved.

The about common toxicity was expected, on-target, mild, transient, and anticipated anemia, which was mitigated by administering priming and maintenance doses in cycle i. Later on the initial priming dose, hemoglobin levels dropped on average past approximately 2 g/dL presumably because of RBC phagocytosis by macrophages in the liver and spleen. However, this was immediately followed by a rapid compensatory reticulocytosis as younger RBCs were released into circulation. Younger RBCs are unperturbed by CD47 occludent because they lack prophagocytic signals that accrue on older RBCs. Despite connected 5F9 dosing, hemoglobin levels typically remained stable across the first calendar week, and in many patients, the anemia gradually resolved to baseline as the circulating RBC population shifted to a younger average age. Hemagglutination on peripheral blood smear was noted in some patients, typically subsequently the outset or second dose, but there was no consequent clan with clinical sequelae. Claret transfusions were infrequently required in this mostly solid tumor population, with four of 62 patients receiving RBC transfusions. However, early on clinical feel with 5F9 in patients with refractory end-stage AML¹⁷ suggests that claret product support tin can readily exist administered to patients who receive 5F9 therapy.

Near 5F9-related AEs were balmy to moderate in severity, and 5F9 infusions were easily administered in an outpatient setting. At dose levels of 20 mg/kg and higher, the unremarkably observed AEs were headache, fatigue, fever, and chills during the infusions, with most occurring inside the first bicycle. Pretreatment with acetaminophen and diphenhydramine lowered the incidence and severity of these reactions, and this pretreatment is recommended before the showtime ii doses of 5F9. A few patients experienced abdominal, dorsum, or breast pains during infusion that were non associated with other clinical findings and oftentimes was mitigated by temporarily stopping or slowing the rate of infusion. No treatment-related autoimmune phenomena (pneumonitis, colitis, or hepatitis) analogous to those reported with programmed cell death 1/programmed cell death-ligand 1 checkpoint inhibitors were observed. Despite the widespread expression of CD47 on normal tissues, patients tolerated 5F9 well presumably because normal cells, unlike their malignant counterparts, lack prophagocytic signals and thus are not susceptible to CD47 occludent. Of notation, no dose-related thrombocytopenia or neutropenia was observed. This favorable safe profile suggests that 5F9 may be readily combined with other antitumor antibodies, which is consistent with emerging clinical reports.¹⁸

Of notation, single-agent 5F9 induced objective tumor responses in two patients, one with clear cell ovarian cancer and one with a fallopian tube cancer. Both patients were heavily pretreated with more than six lines of systemic therapy, including multiple lines of platinum-based chemotherapy. However, all phase I first-in-human studies have limitations because of the heterogeneity of patients who may not reverberate broader phase II and Three study populations because they are selected for more indolent disease, including many who accept participated in multiple prior phase I studies. Therefore, further evaluation of 5F9 is ongoing in an additional cohort of patients with ovarian cancer.

Detailed translational studies that analyze treatment-related changes in the tumor microenvironment in biopsy samples from patients in this trial are ongoing. Boosted trials are ongoing that are evaluating 5F9 therapy in patients with ovarian cancer, AML, and cutaneous T-cell lymphoma. 5F9 generated objective responses in patients with solid tumors in this phase I trial; however, its optimal therapeutic bear upon probable volition be in combination with other anticancer therapies.^eighteen Ongoing combination trials are evaluating 5F9 plus rituximab in B-cell lymphomas (ClinicalTrials.gov identifier: NCT02953509),^eighteen with cetuximab in colorectal cancers (ClinicalTrials.gov identifier: NCT02953782), with azacitidine in treatment-naïve AML and myelodysplastic syndrome (ClinicalTrials.gov identifier: NCT03248479), and with the programmed jail cell death-ligand 1 checkpoint inhibitor avelumab in patients with ovarian cancer (ClinicalTrials.gov identifier: NCT03558139). 5F9 has received fast-track designation by the U.s. Food and Drug Administration for farther development in DLBCL and follicular lymphoma. In summary, enhancement of macrophage phagocytosis of tumor cells past blocking CD47 with 5F9 is a promising new cancer therapeutic strategy.

© 2019 by American Society of Clinical Oncology

Presented at the American Society of Clinical Oncology 2018 Annual Meeting, Chicago, IL, June 1-five, 2018.

Supported by grants from the National Institutes of Health (Stanford Clinical and Translational Research Unit of measurement), California Institute for Regenerative Medicine, and Forty Seven.

Processed as a rapid communication manuscript.

Clinical trial information: NCT02216409.

Encounter accompanying article on page 1012

Conception and design: Branimir I. Sikic, Sumit A. Shah, A. Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Victor Villalobos, Susan Due south. Prohaska, Maureen Howard, Mark P. Chao, Jie Huang, Jie Liu, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Chris H. Takimoto, Mark D. Pegram, Sukhmani K. Padda

Financial support: Branimir I. Sikic, Ravindra Majeti, Chris H. Takimoto

Administrative back up: Branimir I. Sikic, Nehal Lakhani, Sreenivasa R. Chandana, Ravindra Majeti, Chris H. Takimoto, Rhonda Aoki

Provision of study cloth or patients: Branimir I. Sikic, Nehal Lakhani, Drew Rasco, A. Dimitrios Colevas, Timothy O'Rourke, Kyriakos Papadopoulos, George A. Fisher, Susan South. Prohaska, Heather A. Wakelee, Marker D. Pegram

Collection and associates of data: Branimir I. Sikic, Nehal Lakhani, Amita Patnaik, Sumit A. Shah, Sreenivasa R. Chandana, Drew Rasco, A. Dimitrios Colevas, Timothy O'Rourke, Sujata Narayanan, Kyriakos Papadopoulos, George A. Fisher, Victor Villalobos, Maureen Howard, Muralidhar Beeram, Mark P. Chao, Balaji Agoram, James Y. Chen, Jie Huang, Matthew Axt, Jens-Peter Volkmer, Chris H. Takimoto, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Sukhmani K. Padda

Data analysis and interpretation: Branimir I. Sikic, Nehal Lakhani, Amita Patnaik, Sumit A. Shah, A. Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Maureen Howard, Mark P. Chao, Balaji Agoram, James Y. Chen, Jie Huang, Jens-Peter Volkmer, Irving 50. Weissman, Chris H. Takimoto, Heather A. Wakelee, Mark D. Pegram, Sukhmani M. Padda

Manuscript writing: All authors

Last approving of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Beginning-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibiotic Hu5F9-G4 in Patients With Advanced Cancers

The post-obit represents disclosure data provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more data nigh ASCO'south disharmonize of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Branimir I. Sikic

Consulting or Advisory Role: Threshold Pharmaceuticals, Allowed Blueprint

Research Funding: Forty Vii (Inst), Celldex Therapeutics (Inst), Gilead Sciences (Inst), Basilea Pharmaceutica (Inst), Genentech (Inst), Roche (Inst), Sanofi (Inst)

Nehal Lakhani

Research Funding: Alexo Therapeutics (Inst), Ascentage Pharma (Inst), Asana BioSciences (Inst), BeiGene (Inst), Constellation Pharmaceuticals (Inst), Alexion Pharmaceuticals (Inst), Cerulean Pharma (Inst), 40 Vii (Inst), Loxo Oncology (Inst), Macrogenics (Inst), Merck (Inst), Pfizer (Inst), Regeneron Pharmaceuticals (Inst), TaiRx (Inst), Apexian Pharmaceuticals (Inst), Germination Biologics (Inst), Coordination Therapeutics (Inst), Symphogen (Inst), CytomX Therapeutics (Inst), InhibRx (Inst), Incyte (Inst), Jounce Therapeutics (Inst), Livzon Pharmaceutical Group (Inst), Northern Biologics (Inst), TESARO (Inst)

Amita Patnaik

Consulting or Advisory Role: Bayer AG, Novartis, Genentech (I), Roche (I), Merck

Research Funding: Merck (Inst), Pfizer (Inst), Eli Lilly (Inst), Plexxikon (Inst), Corvus Pharmaceuticals (Inst), TESARO (Inst), AbbVie (Inst), Forty Seven (Inst), Five Prime Therapeutics (Inst), Infinity Pharmaceuticals (Inst), Proximagen (Inst), Pieris Pharmaceuticals (Inst), Surface Oncology (Inst), Livzon Pharmaceutical Group (Inst), Vigeo Therapeutics (Inst), Astellas Pharma (Inst), KLUS Pharma (Inst), Symphogen (Inst), Syndax (Inst)

Sumit A. Shah

Stock and Other Buying Interests: Grand Rounds

Sreenivasa R. Chandana

Consulting or Advisory Office: Ipsen, AstraZeneca, Eli Lilly

Speakers' Bureau: Ipsen

Enquiry Funding: Novocure (Inst)

Drew Rasco

Employment: First

Consulting or Advisory Role: TaiRx, Boehringer Ingelheim, Eli Lilly

Research Funding: Celgene (Inst), Millennium Pharmaceuticals (Inst), Rexahn Pharmaceuticals (Inst), Santa Maria Biotherapeutics (Inst), Five Prime Therapeutics (Inst), Pharmacyclics (Inst), Asana Biosciences (Inst), Eisai (Inst), Aeglea BioTherapeutics (Inst), Merck (Inst), Ascentage Pharma (Inst), Macrogenics (Inst), Apexian Pharmaceuticals (Inst), Birdie Pharmaceuticals (Inst), AbbVie (Inst), Constellation Pharmaceuticals (Inst), Syndax (Inst)

Travel, Accommodations, Expenses: Asana BioSciences

A. Dimitrios Colevas

Stock and Other Ownership Interests: Gilead Sciences, Pharmacyclics

Consulting or Advisory Role: COTA, KeyQuest Wellness, Loxo Oncology, Atara Biotherapeutics, Aduro Biotech, Cue Biopharma, Pfizer

Inquiry Funding: Bristol-Myers Squibb, AstraZeneca, Innate Pharma, CellSight Technologies, Tessa Therapeutics

Timothy O'Rourke

Research Funding: Asana BioSciences (Inst)

Sujata Narayanan

Employment: Genentech

Stock and Other Ownership Interests: Roche

Kyriakos Papadopoulos

Consulting or Advisory Office: Bayer AG (Inst), ArQule (Inst)

Research Funding: AbbVie (Inst), MedImmune (Inst), Daiichi Sankyo (Inst), Regeneron Pharmaceuticals (Inst), Sanofi (Inst), ARMO BioSciences (Inst), ArQule (Inst), Calithera Biosciences (Inst), Curegenix (Inst), Incyte (Inst)Merck (Inst), Peloton Therapeutics (Inst), ADC Therapeutics (Inst), 3D Medicines (Inst), Formation Biologics (Inst), EMD Serono (Inst), Syros Pharmaceuticals (Inst), Mersana (Inst), OncoMed (Inst), MabSpace Biosciences (Inst), Jounce Therapeutics (Inst)

George A. Fisher

Stock and Other Ownership Interests: Seattle Genetics (I)

Honoraria: Merck, Genentech, Ipsen, Novartis

Consulting or Advisory Role: Ipsen, Genentech, Roche, Merck, Jounce Therapeutics

Research Funding: Newlink Genetics (Inst), XBiotech (Inst), Genentech (Inst), Roche (Inst), EpicentRx (Inst), Merck (Inst), Forty Seven (Inst), Aduro Biotech (Inst), Novartis (Inst)

Travel, Accommodations, Expenses: Merck Sharp & Dohme

Victor Villalobos

Consulting or Advisory Office: Janssen Pharmaceuticals, Eli Lilly, Novartis, AbbVie, Ignyta, Agios, Epizyme

Travel, Accommodations, Expenses: Eli Lilly, Janssen Pharmaceuticals, Xencor, GenMab, Apizyme

Susan S. Prohaska

Employment: Forty Seven

Stock and Other Buying Interests: Twoscore Vii, Amgen

Consulting or Informational Role: Forty Vii

Patents, Royalties, Other Intellectual Property: Inventor on patent adult at Stanford and assigned to Forty Vii

Other Relationship: Stanford University

Maureen Howard

Stock and Other Ownership Interests: Forty Seven

Consulting or Advisory Role: Cartherics

Patents, Royalties, Other Intellectual Property: Methods for Achieving Therapeutically Effective Doses of Anti-CD47 Agents, Stanford University, November 2014, WO 2014/1494772; Methods for Achieving Therapeutically Effective Doses of Anti-CD47 Agents, Stanford Academy, Feb 2014, US 502667359

Muralidhar Beeram

Honoraria: Genentech

Consulting or Advisory Role: Novartis (I)

Speakers' Bureau: Genentech

Research Funding: Eli Lilly (Inst), Zymeworks (Inst), Mersana Therapeutics (Inst)

Mark P. Chao

Employment: Forty Seven

Leadership: Forty Seven

Stock and Other Ownership Interests: 40 Vii, Hepatx

Honoraria: D2G Oncology

Consulting or Advisory Role: Bubble Bioengineering

Patents, Royalties, Other Intellectual Belongings: Inventor on several patents from Stanford University licensed to Forty Seven, inventor on patents generated from Forty Vii

Travel, Accommodations, Expenses: Forty Seven

Balaji Agoram

Employment: Forty Vii

Stock and Other Buying Interests: Forty 7

James Y. Chen

Employment: Xl Seven

Stock and Other Ownership Interests: Forty 7

Consulting or Informational Role: 40 Seven

Research Funding: 40 Seven

Travel, Accommodations, Expenses: Xl 7

Jie Huang

Employment: Forty Seven

Travel, Accommodations, Expenses: Twoscore Seven

Matthew Axt

Employment: Twoscore Seven

Employment: Kaiser Permanente (I)

Stock and Other Buying Interests: Forty Seven

Jie Liu

Stock and Other Ownership Interests: Twoscore Seven

Patents, Royalties, Other Intellectual Property: Stanford/Xl 7: CD47, SIRPa, CD99

Jens-Peter Volkmer

Employment: Forty Seven

Stock and Other Ownership Interests: Forty Seven

Patents, Royalties, Other Intellectual Holding: Co-inventor on technologies that have been licensed to Forty Seven

Ravindra Majeti

Employment: Roche (I), Genentech (I)

Leadership: Forty Seven

Stock and Other Ownership Interests: 40 Seven, Roche (I), Genentech (I), Amgen (I), Imago BioSciences

Honoraria: Roche, Genentech, Pharmacyclics

Consulting or Informational Office: 40 Vii, Biomarin

Research Funding: Celgene, Bluestar Genomics

Patents, Royalties, Other Intellectual Property: Numerous patents related to CD47 targeting and therapeutics that have been licensed to Forty 7

Irving L. Weissman

Employment: Forty Vii

Leadership: Forty 7

Stock and Other Ownership Interests: Twoscore Seven

Consulting or Advisory Role: Forty 7

Patents, Royalties, Other Intellectual Property: Many patents licensed by Stanford to Forty Seven, patents licensed to Systemix that were sold to Sandoz and Novartis, inventions for Systemix, patent awaiting in the brain stem cell field as function of Stem Cells cofounded in 1997 and sold in 2016

Travel, Accommodations, Expenses: 40 Vii

Other Relationship: Stem Cells (I)

Chris H. Takimoto

Employment: Forty 7

Leadership: Twoscore Seven

Stock and Other Ownership Interests: Johnson & Johnson, Forty Vii

Patents, Royalties, Other Intellectual Property: Patent proposals filed related to using anti-CD47 antibodies equally cancer therapy at Forty Seven

Travel, Accommodations, Expenses: Forty Seven

Dana Supan

Inquiry Funding: 40 Seven (Inst)

Heather A. Wakelee

Honoraria: Novartis, AstraZeneca

Inquiry Funding: Genentech (Inst), Roche (Inst), Pfizer (Inst), Eli Lilly (Inst), Celgene (Inst), AstraZeneca (Inst), MedImmune (Inst), Exelixis (Inst), Novartis (Inst), Clovis Oncology (Inst), Xcovery (Inst), Bristol-Myers Squibb (Inst), Gilead Sciences (Inst), Pharmacyclics (Inst), ACEA Biosciences (Inst)

Travel, Accommodations, Expenses: AstraZeneca

Rhonda Aoki

Inquiry Funding: Xl Seven (Inst), Celldex Therapeutics (Inst)

Mark D. Pegram

Employment: Loxo Oncology (I)

Consulting or Advisory Role: Genentech, Pfizer, Novartis, Amgen, AstraZeneca, Merck

Travel, Accommodations, Expenses: Genentech, Pfizer, Novartis, DAVA Pharmaceuticals

Sukhmani G. Padda

Consulting or Advisory Role: Janssen Pharmaceuticals, G1 Therapeutics, AstraZeneca, AbbVie

Research Funding: EpicentRx (Inst), Forty Seven (Inst), Bayer AG (Inst)

Patient Eligibility

Additional patient eligibility criteria included having malignancy assessable for response by Response Evaluation Criteria in Solid Tumors (RECIST) for solid tumors or International Working Group criteria for lymphomas; ECOG operation status 0–2; life expectancy at least iii months, and negative urine or serum pregnancy tests for all women of child-bearing potential.Exclusion criteria included primary brain tumors, patients with brain metastases, red blood cells (RBCs) transfusion dependence, hemoglobin < 9.v g/dL, neutrophils < i.0 × 109/mL, AST/ALT > 5 times upper limits of normal (ULN), Bilirubin > 2.five times ULN, serum creatinine > ane.v times ULN, and pregnant medical conditions that would essentially increase the medical risks of participation in the study.

Methods

Dose-limiting toxicity exceptions: Grade 3 anemia; Grade three nausea, vomiting, diarrhea, or infusion reactions in the absence of premedication (including influenza-like symptoms, myalgias, fever, chills, headache, or acute pain) that resolves to ≤ Grade 2 inside ≤ 72 hours after medical management (eg, supportive care) has been initiated; Grade 3 fatigue that resolves to ≤ Grade 2 within 2 weeks on report; Course 3 hyperbilirubinemia, isolated electrolyte abnormalities, or alanine aminotransferase and/or aspartate aminotransferase elevations that resolve to ≤ Grade two with supportive care within 72 hours and is not associated with other clinically significant consequences; Grade 3 tumor lysis syndrome or related electrolyte disturbances (hyperkalemia, hypophosphatemia, hyperuricemia) that resolve to ≤ Course 2 inside 7 days; Class 3 or 4 lymphopenia.

Routine Laboratory Assessments

Laboratory assessments included routine claret counts with reticulocyte counts, general chemical science panels, serum uric acrid, phosphorous, haptoglobin, D-Dimer, thrombin fourth dimension, plasma fibrinogen, serum folic acid, prothrombin time, activated fractional thromboplastin time, full atomic number 26 and transferrin saturation, and urinalysis. All patients had a blood type and screen and direct antigen test performed at screening. Electrocardiograms were obtained at baseline and days viii, 29 and 57 of therapy. Peripheral blood smears were evaluated for claret cell morphology pre- and post-5F9 dosing on days ane and 8 and on days 2, 4, eight, 11, 15, 22 and 29. Loftier resolution retinal photographs were performed at screening, and on days 1, ii, four, viii, 9, xi and xv to appraise for retinal microangiopathy; nonetheless, retinal imaging was halted in Role B due to a lack of correlative findings.

Pharmacokinetics and Anti-Drug Antibodies

Blood samples for pharmacokinetics (PK) monitoring were collected on twenty-four hours one pre-dose, and at the end of infusion and on twenty-four hours 8 at pre-dose and 0, 1, and 2 hours later the stop of infusion. Additional PK samples were collected on days 9 and 30, and pre- and post-dose on days xi (if dosed), 15, 22, 29, 36, 43, 50, and 57 and finally at the finish of study treatment. Samples were shipped to a central laboratory for assay of 5F9 concentration in serum using a validated ELISA Assay.¹⁵ The assay was specific to 5F9 and had a lower limit of quantification of approximately 200 ng/mL. Noncompartmental analysis (NCA) was performed using NCA for R software packet to guess PK parameters such as terminal half-life and area-under-the-concentration (AUC) curve.¹⁹

Anti-drug antibodies (ADA) were collected pre-dose and then every iv weeks through calendar week 17, and and so on weeks 25, 33, 49 and 30 days after the last dose of 5F9. Samples were shipped to a central laboratory for ADA assay.¹⁵ The ADA analysis followed a 3-tiered approach, consisting of screening, confirmatory, and titer steps with pre-specified simulated positive rates of five% and i% for the screening and confirmatory steps, respectively. The cutting points were generated using in-study samples.

Pharmacodynamics and Tumor Biopsies

Blood samples for CD47 receptor occupancy assessments on RBC and WBC were collected on twenty-four hours 1 and 8 pre- and mail-dosing with 5F9 and on days 15, 22, 29, 36, 57 and end of study treatment. Receptor occupancy measurements were quantitated by using a period cytometry analysis with a tagged fluorescent anti-CD47 antibody to assess saturation of CD47 binding sites on RBC and WBC obtained from patients.

In the mandatory tumor biopsy cohort, patients were required to undergo mandatory tumor biopsies that were obtained pre-handling and during calendar week vi of handling. Tissue specimens were formalin- fixed and alkane-embedded and subjected to immunohistochemical stains using an anti-IgG4 antibody. Because the levels of endogenous IgG4 levels are low in about tissues, treatment related changes could observe the presence of 5F9 in tissues during handling.

TABLE A1. Summary of Geometric Hateful (Geometric %CV) Cmax and AUC Values after the First (Priming), Second, and 5th Doses at All Dose Levels (Study SCI-CD47-001; Data Supplement)

ACKNOWLEDGMENT

Nosotros give thanks Susan Jerian, MD, and David Essayan, Physician, of ONCORD for their advice on study design. We are nearly grateful to the participating patients and their family members and to all the nurses, investigators, and study staff who contributed to this clinical study.

REFERENCES

Section:

i.	Chocolate-brown EJ , Frazier WA : Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 11:130-135, 2001 Crossref, Medline, Google Scholar
ii.	Chao MP , Alizadeh AA , Tang C , et al: Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142:699-713, 2010 Crossref, Medline, Google Scholar
3.	Willingham SB , Volkmer JP , Gentles AJ , et al: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for homo solid tumors. Proc Natl Acad Sci U South A 109:6662-6667, 2012 Crossref, Google Scholar
4.	Chao MP, McKenna KM, Cha A, et al: The anti-CD47 antibiotic Hu5F9-G4 is a novel immune checkpoint inhibitor with synergistic efficacy in combination with clinically active cancer targeting antibodies. Cancer Immunol Res four, 2016 (abstr PR13) Google Scholar
five.	Majeti R , Chao MP , Alizadeh AA , et al: CD47 is an agin prognostic cistron and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138:286-299, 2009 Crossref, Medline, Google Scholar
half-dozen.	Chen Q , Fang Ten , Jiang C , et al: Thrombospondin promoted anti-tumor of adenovirus-mediated calreticulin in breast cancer: Human relationship with anti-CD47. Biomed Pharmacother 73:109-115, 2015 Crossref, Google Scholar
7.	Chao MP , Jaiswal South , Weissman-Tsukamoto R , et al: Calreticulin is the ascendant pro-phagocytic signal on multiple homo cancers and is counterbalanced by CD47. Sci Transl Med ii:63ra94, 2010 Crossref, Google Scholar
eight.	Oldenborg PA , Zheleznyak A , Fang YF , et al: Role of CD47 as a marking of self on red blood cells. Science 288:2051-2054, 2000 Crossref, Google Scholar
9.	Liu J , Wang 50 , Zhao F , et al: Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One 10:e0137345, 2015 Medline, Google Scholar
10.	Olsson M , Oldenborg PA : CD47 on experimentally senescent murine RBCs inhibits phagocytosis post-obit Fcgamma receptor-mediated but not scavenger receptor-mediated recognition by macrophages. Blood 112:4259-4267, 2008 Crossref, Google Scholar
11.	Simon R , Freidlin B , Rubinstein 50 , et al: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138-1147, 1997 Crossref, Medline, Google Scholar
12.	Le Tourneau C , Lee JJ , Siu LL : Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101:708-720, 2009 Crossref, Medline, Google Scholar
thirteen.	Eisenhauer EA , Therasse P , Bogaerts J , et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 Crossref, Medline, Google Scholar
14.	Barrington SF , Mikhaeel NG , Kostakoglu L , et al: Role of imaging in the staging and response assessment of lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32:3048-3058, 2014 Link, Google Scholar
15.	Agoram B, Wang B, Sikic BI, et al: Pharmacokinetics of Hu5F9-G4, a starting time-in-class anti-CD47 antibiotic, in patients with solid tumors and lymphomas. J Clin Oncol 36, 2018 (suppl; abstr 2525) Google Scholar
16.	Wang W , Wang EQ , Balthasar JP : Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548-558, 2008 Crossref, Medline, Google Scholar
17.	Vyas P, Knapper South, Kelly R, et al: Initial phase one results of the first-in-course anti-CD47 antibody Hu5F9-G4 in relapsed/refractory acute myeloid leukemia patients. EHA Learning Middle 2018 (abstr PF232) Google Scholar
18.	Advani R , Flinn I , Popplewell L , et al: CD47 occludent by Hu5F9-G4 and rituximab in non-Hodgkin'due south lymphoma. Due north Engl J Med 379:1711-1721, 2018 Crossref, Medline, Google Scholar
19.	Buckeridge C , Duvvuri S , Denney WS : Unproblematic, automatic noncompartmental analysis: The PKNCA R package. J Pharmacokinet Pharmacodyn 42:S65, 2015 Google Scholar

keithlonts1969.blogspot.com

Source: https://ascopubs.org/doi/10.1200/JCO.18.02018

Share this post