| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Head and Neck Squamous Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer in the Head and Neck |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety Run-in Cohorts:
To evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of magrolimab in combination with the following:
- Pembrolizumab + 5-fluorouracil (5-FU) + platinum
- Docetaxel
Phase 2 Cohorts:
- To evaluate the progression-free survival (PFS) with magrolimab in combination with pembrolizumab + 5-FU + platinum versus pembrolizumab + 5-FU + platinum by independent central review (Phase 2 Cohort 1)
- To evaluate the efficacy of magrolimab in combination with pembrolizumab, if this optional cohort is opened, and magrolimab in combination with docetaxel as determined by the
investigator-assessed objective response rate (ORR) (Phase 2 Cohorts 2 and 3) |
|
| E.2.2 | Secondary objectives of the trial |
Safety Run-in Cohorts:
To evaluate the pharmacokinetics (PK) and immunogenicity of magrolimab in combination with anticancer therapies
Phase 2 Cohorts:
-To evaluate PFS for magrolimab + zimberelimab + platinum + 5-FU
versus pembrolizumab + platinum + 5-FU by independent central review
- To evaluate ORR by independent central review
- To evaluate PFS by investigator assessment
- To evaluate additional measures of efficacy, including duration of response (DOR) and overall survival (OS)
- To evaluate the PK and immunogenicity of magrolimab in combination with anticancer therapies
- To evaluate patient-reported outcomes (PROs)/quality-of-life measures |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All Patients
1) Patient has provided informed consent.
2) Patient is willing and able to comply with clinic visits and
procedures outlined in the study protocol.
3) Male or female ≥ 18 years of age
4) Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5) Laboratory measurements, blood counts:
a) Hemoglobin must be ≥ 9 g/dL prior to initial dose of study treatment. Red blood cell transfusions are allowed to meet hemoglobin eligibility within limits set per Exclusion Criterion #6.
b) Absolute neutrophil count ≥ 1.5 x 10^9
c) Platelets ≥ 100 x 10^9
6) Laboratory measurements, renal function:
a) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or if elevated, a calculated glomerular filtration rate > 40 mL/min/1.73m^2
7) Laboratory measurements, hepatic function:
a) Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN or ≤ 5 x ULN in patients with liver metastases
b) Total bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN and primarily unconjugated if patient has a documented history of Gilbert’s syndrome or genetic equivalent
8) Laboratory measurements, coagulation function:
a) International normalized ratio or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulation therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use for anticoagulants
b) Activated partial thromboplastin time or PTT ≤ 1.5 x ULN unless patient is receiving anticoagulation therapy, as long as PT or PTT is within therapeutic range of intended use for anticoagulants
9) Pretreatment blood cross-match completed
10) Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
11) Measurable disease according to RECIST, version 1.1
12) Note: inclusion Criterion #12 was removed in Protocol Amendment 3
and relocated to Inclusion Criterion #13d
Safety Run-in Cohort 1, Pre-expansion Safety Run-in Cohort for Magrolimab + Pembrolizumab (if Applicable), and Phase 2 Cohorts 1 and 2
In addition to meeting the inclusion criteria for all patients, patients who
are enrolled into Safety Run-in 1, the pre-expansion safety run-in for
magrolimab + pembrolizumab (if applicable), and Phase 2 Cohorts 1 and
2 must fulfill the following cohort-specific inclusion criterion:
13) Patients with histologically or cytologically confirmed metastatic or locally recurrent HNSCC that is considered incurable by local therapies
a) Patients should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy that was completed more than 6 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed.
b) Eligible primary tumor locations include oropharynx, oral cavity, hypopharynx, and larynx.
c) Patients may not have a primary tumor site of nasopharynx (any histology).
d) Patients must be willing to provide baseline tumor tissue from a core
or excisional biopsy (fine needle aspirate is not adequate). A newly
obtained biopsy (within 90 days prior to study treatment start) is
strongly preferred, but an archival sample is acceptable. For archival
samples submitted in lieu of newly obtained biopsies, tissue collected
within 6 months prior to study treatment start is strongly preferred
whenever possible. Patients will also be requested to consent to a
mandatory on-treatment tumor biopsy, unless not feasible as
determined by the investigator and discussed with the sponsor.
Safety Run-in 1 and Phase 2 Cohort 1:
In addition to meeting the inclusion criteria for all patients, patients who
are enrolled into Safety Run-in 1 and Phase 2 Cohort 1 must fulfill the
following cohort-specific inclusion criterion:
14) Patients with HNSCC per inclusion criterion 13 regardless of PD-L1 status
Pre-expansion Safety Run-in Cohort for Magrolimab + Pembrolizumab (if Applicable) and Phase 2 Cohort 2
In addition to meeting the inclusion criteria for all patients, patients who are enrolled into the pre-expansion safety run-in cohort for
magrolimab + pembrolizumab (if applicable) and Phase 2 Cohort 2
must fulfill the following cohort specific inclusion criterion:
15) Patients with HNSCC per inclusion criterion 13 with a PD-L1 CPS ≥ 1
Safety Run-in Cohort 2 and Phase 2 Cohort 3:
In addition to meeting the inclusion criteria for all patients, patients who are enrolled into Safety Run-in Cohort 2 and Phase 2 Cohort 3 must fulfill the following cohort-specific inclusion criterion:
16) Patients with histologically or cytologically confirmed locally advanced/mHNSCC regardless of PD-L1 status with at least 1 and no more than 2 lines of prior systemic anticancer therapy in the locally advanced/metastatic setting
a) Eligible primary tumor locations include oropharynx, oral cavity, hypopharynx, and larynx.
Please see protocol for full list of inclusion criteria |
|
| E.4 | Principal exclusion criteria |
All Patients:
1) Prior radiation therapy (or other nonsystemic therapy) within 2 weeks prior to enrollment. Patients who are candidates for curative radiation therapy are not eligible.
2) Patient has not fully recovered (ie, ≤ Grade 1 at baseline) from AEs due to a previously administered treatment.
a) Note: Patients with ≤ Grade 2 neuropathy, ≤ Grade 2 alopecia, or laboratory values in inclusion criteria 5 through 8 are exceptions to this criterion and may qualify for the study.
b) Note: If a patient received major surgery, he or she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
3) Positive serum pregnancy test
4) Breastfeeding female
5) Active central nervous system (CNS) disease (patients with asymptomatic and stable, treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks are not considered active)
6) Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of packed RBCl transfusions during the 4-week period prior to screening. RBC transfusions are permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criterion.
7) History of hemolytic anemia, autoimmune thrombocytopenia, or Evans syndrome in the last 3 months
8) Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
a) For Phase 2 Cohort 1, complete absence of dihydropyrimidine
dehydrogenase (DPD) activity. If DPD status is not known, testing for
DPD status should be done during the screening period where such
testing is standard of care.
9) Prior treatment with cluster of differentiation 47 or signal regulatory protein alpha-targeting agents
10) Prior anticancer therapy including, but not limited to, chemotherapy, immunotherapy, or investigational agents within 4 weeks prior to magrolimab treatment
11) Life expectancy of less than 3 months and/or rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator
12) Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy. Corticosteroid use as a premedication for allergic reactions or for prophylactic management of AEs related to the chemotherapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved with approval by the sponsor.
13) Active autoimmune disease that has required systemic treatment in the past 2 years (ie, use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
14) Prior allogeneic tissue/solid organ transplant
15) History of (noninfectious) pneumonitis that required steroids or current pneumonitis
16) Active, uncontrolled infection or infection requiring systemic therapy within ≤ 7 days of study entry
17) Live vaccine within 30 days of start of study treatment
18) Current participation in another interventional clinical study
19) Known inherited or acquired bleeding disorders
20) Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV.
21) Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which patients are not on active anticancer therapies and who are in complete remission for over 5 years
22) Known HIV infection. HIV testing will be performed at screening only if required by local guidelines or institutional standards.
23) Known positivity for hepatitis B or C infection. Patients not currently on antiviral therapy and who have an undetectable viral load in the prior 3 months may be eligible for the study. Hepatitis B or C testing is not required. Patients with serologic evidence of prior vaccination to HBV (ie, hepatitis B surface antigen negative and antibody against hepatitis B surface antigen positive) may participate.
Safety Run-in Cohort 1, Pre-expansion Safety Run-in Cohort for Magrolimab + Pembrolizumab (if Applicable), and Phase 2 Cohorts 1 and 2:
24) Progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
25) Prior treatment with any of the following:
Please see protocol for complete exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Run-in Cohorts:
Incidence of adverse events (AEs) and laboratory abnormalities defined as dose-limiting toxicities (DLTs) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0
Phase 2 Cohorts:
- PFS, defined as the time from the date of randomization until the earliest date of documented disease progression, as assessed by independent central review, or death from any cause, whichever occurs first (Phase 2 Cohort 1, Arm A versus Arm B)
- ORR, defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) as measured by response evaluation criteria in solid tumors (RECIST), version 1.1, as determined by investigator assessment (Phase 2 Cohorts 2 and 3) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Incidence of AEs assessed for duration of the study at every visit after the first dose of study treatment through 30 days after the last dose of
study treatment (or 90 days after last dose for zimberelimab). Clinical laboratory tests are carried out at most study visits, following the Schedule of Assessments within the protocol. To assess efficacy, clinical and radiographic results are collected at screening, every 6 weeks (2 cycles) until Cycle 12 and then every 9 weeks (3 cycles) during the study, and at the end-of-treatment visit. For Phase 2 Cohort 1, the primary efficacy endpoint will be PFS by independent central review. For Phase 2 Cohorts 2 and 3, assessment of response will be measured by RECIST, version 1.1, as determined by investigator assessment (primary efficacy endpoint). |
|
| E.5.2 | Secondary end point(s) |
Safety Run-in Cohorts:
Magrolimab concentration versus time and antidrug antibodies (ADAs) to magrolimab
Phase 2 Cohorts:
-PFS, as assessed by independent central review, or death from any
cause, whichever occurs first (Phase 2 Cohort 1, Arm C versus
concurrent Arm B)
- ORR, as determined by independent central review
- PFS from date of randomization (Phase 2 Cohort 1) or date of dose initiation (Phase 2 Cohort 2 and Phase 2 Cohort 3) until the earliest date of documented disease progression as determined by investigator assessment per RECIST, version 1.1, or death from any cause, whichever occurs first
- DOR, defined as time from first documentation of CR or PR to the earliest date of documented disease progression or death from any cause, whichever occurs first
- OS, defined as time from date of randomization (Phase 2 Cohort 1) or date of dose initiation (Phase 2 Cohort 2 and Phase 2 Cohort 3) to death from any cause
- Magrolimab concentration versus time and ADAs to magrolimab
- PRO assessment (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire [EORTC QLQ-C30], European Organisation for Research and Treatment of Cancer Quality of Life - Head and Neck Module [EORTC QLQ-H&N35], and 5-level EuroQol 5 dimensions questionnaire [EQ-5D-5L]) scores |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Magrolimab concentrations and peripheral blood for immunogenicity assessments for ADAs will be assessed approximately once a cycle until study discontinuation, , according to the Schedule of Assessments within the protocol.
To assess efficacy, clinical and radiographic results are collected at screening, every 6 weeks (2 cycles) until Cycle 12 and then every 9 weeks (3 cycles) during the study, and at the end-of-treatment visit. For Phase 2 Cohorts 2 and 3, assessment of response will be measured by RECIST, version 1.1, as determined by independent central review (secondary efficacy endpoint). Survival follow-up is carried out every 2 months after safety follow-up visit until death or end of study. PRO assessment scores are collected at every cycle until the last dose of treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Hong Kong |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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