MERIDIAN: Molecular Residual Disease Interception in Locoregionally-Advanced High Risk HPV+ and HPV- HNSCC
Study Details
Study Description
Brief Summary
This is a phase II, open-label study to assess the efficacy of monalizumab and cetuximab in terms of molecular residual disease (MRD) clearance and treatment outcome in patients with MRD after definitive treatment for high risk locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). MRD is defined as ctDNA detection in plasma after definitive treatment. Approximately 200 patients are expected to be enrolled.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a phase II, open-label study to assess the efficacy of monalizumab and cetuximab in terms of molecular residual disease (MRD) clearance and treatment outcome in patients with MRD after definitive treatment for high risk locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). MRD is defined as ctDNA detection in plasma after definitive treatment. Approximately 200 patients are expected to be enrolled.
The study is divided in 5 parts:
Part A and Part B are common for all patients in the study, which are defined as the periods of definitive treatment and post definitive treatment. Definitive treatment will be either surgery followed by radiation or chemoradiation; definitive radiation or definitive chemoradiation according to standard of care (SOC) in our institution. A baseline ctDNA sample collection and CT staging will be done before treatment. ctDNA analysis will be performed in Part B at approximately week 5 and at week 10 of this period, and patients will be classified as MRD positive or MRD negative at the end of this part.
Part C is the randomized and interventional part of the study (n=60) for patients with MRD. The patient will be randomized 3:1 to Arm A (treatment with monalizumab 750 mg IV Q2W and cetuximab 500 mg/m2 IV Q2W) or Arm B (observation). Patients in Arm A will continue treatment until the occurrence of any of these circumstances: after completion of 8 cycles, intolerable toxicity or patient decision. ctDNA analysis will be done at week 9 of Part C.
Part D is the follow up part for patients with MRD. Two ctDNA samples will be analyzed at week 2 and at week 10 of Part D. A final sample will be also collected if the patient has radiological or clinical progression. A CT/MRI scan will be performed at week 2 of Part D and, if clinically needed, according to SOC.
Part E is the observational follow up part for patients without MRD. A ctDNA sample will be collected at radiological or clinical progression.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: MRD positive Cohort - Arm A (treatment) monalizumab 750 mg every two weeks (x 8 doses) and cetuximab 500mg/m2 every two weeks (x 8 doses) for a total of 8 treatment cycles (16 weeks). |
Biological: Monalizumab
Monalizumab is a first-in-class ICI targeting NKG2A. It is a non-depleting humanized IgG4 monoclonal antibody (mAb) that binds with high affinity and specificity to, and blocks the inhibitory activity of the CD94/NKG2A receptor resulting in the stimulation of the cytolytic activity of CD94/NKG2A expressing NK cells and CD8+ T cells. Monalizumab is being developed for the treatment of various cancers, including solid tumors and hematologic malignancies either as monotherapy or in combination. Human leukocyte antigen E (HLA-E), a nonclassical major histocompatibility complex class I molecule, is expressed on tumor cells in 78% to 86% of patients with HNSCC (André et al., 2018; Näsman et al., 2013; Silva et al., 2011). HLA-E is the ligand of the inhibitory CD94/NKG2A receptors that are found on NK cells and intratumoral CD8+ T cells in a variety of tumor types, including HNSCC (Braud et al., 1998; Gooden et al., 2011; Katou et al., 2007; N. Lee et al., 1998).
Biological: Cetuximab
Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the EGFR. The EGFR is an important regulator of cell growth and differentiation. Upon ligand binding, EGFR homodimerizes or interacts with other HER members, i.e., HER2 and HER3, to form heterodimers. This results in activation of downstream signaling cascades such as the RAS/ERK pathway and PI3K/AKT pathway, thereby controlling many biological processes. These pathways play a pivotal role in multiple tumor types, including head and neck cancers, and are frequently dysregulated via overexpression or autocrine stimulation. Targeting EGFR, eg, with an anti-EGFR mAb like cetuximab, is an important treatment modality for head and neck cancers. Several studies have suggested that antibody-dependent cellular cytotoxicity (ADCC) activity is important for cetuximab clinical efficacy and is dependent on tumor cell surface EGFR expression(Kol et al., 2017).
Other Names:
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| No Intervention: MRD positive Cohort - Arm B (observation)
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| No Intervention: MRD negative Cohort
|
Outcome Measures
Primary Outcome Measures
- Efficacy (in terms of ctDNA clearance) of monalizumab and cetuximab compared to observation (Standard of Care, SOC) in LA-HNSCC patients who have MRD (MRD+) after definitive treatment. [3 years]
Clearance of bespoke ctDNA at different time points (week 2 and week 10 after the end of MRD treatment). ctDNA clearance is defined as no detection of ctDNA in both of these two consecutive determinations.
Secondary Outcome Measures
- Efficacy (in terms of delaying or preventing radiological recurrence of disease or death) of monalizumab and cetuximab compared to observation (SOC) in MRD+ LA-HNSCC patients after definitive treatment. [3 years]
Disease free survival (DFS) at 12 months.
- Efficacy (in terms of MRD control) of monalizumab and cetuximab compared to observation (SOC) in MRD+ LA-HNSCC patients after definitive treatment. [3 years]
Time to MRD control failure in MRD+ patients. MRD control failure is defined as two consecutive increases in ctDNA levels (week 2 and week 10 in Part D).
- Efficacy (in terms of median DFS and OS) of monalizumab and cetuximab compared to observation (SOC) in MRD+ LA-HNSCC patients after definitive treatment. [3 years]
Median DFS and OS in MRD+ patients.
- Safety and tolerability of monalizumab and cetuximab in MRD+ LA-HNSCC patients after definitive treatment and randomized to receive this combination. [3 years]
Number and severity of treatment related adverse events according to CTCAE v5.0.
Other Outcome Measures
- Predictive value (in terms of predicting radiological recurrence of disease or death) of HPV DNA in patients with HPV positive LA-HNSCC treated with cetuximab and monalizumab compared to observation (SOC). [3 years]
Changes in HPV DNA in MRD+ HPV+ patients treated with monalizumab and cetuximab or under observation and correlation of such changes with DFS.
- Predictive value (in terms of predicting radiological recurrence of disease or death) of methylated ctDNA in MRD+ LA-HNSCC patients treated with monalizumab and cetuximab compared to observation (SOC). [3 years]
Changes in methylated ctDNA in MRD+ patients treated with monalizumab and cetuximab or under observation, and correlation of such changes with bespoke ctDNA and with DFS.
- Kinetics of bespoke ctDNA and HPV DNA in LA-HNSCC patients after definitive therapy [2 years]
Changes in quantitative bespoke ctDNA and HPV DNA measurements before treatment and at W4-6 and W 8-12 (Parts A and B).
- Kinetics of bespoke ctDNA and HPV DNA in MRD+ LA-HNSCC patients who are treated with monalizumab and cetuximab compared to observation (SOC). [3 years]
Changes in quantitative bespoke ctDNA and HPV DNA measurements during and after treatment/observation (Parts C and D).
- Correlation between radiological response and changes in quantitative bespoke ctDNA and HPV DNA measurements. [3 years]
Correlation between radiological response and changes in quantitative bespoke ctDNA and HPV DNA measurements.
- Health related quality of life at various time points throughout the study using the FACT-ICM tool. [3 years]
Overall mean changes in FACT-ICM scores in MRD+ LA-HNSCC patients from baseline (of Part A for Part C for FACT-ICM) and cross sectional comparisons including during and after cetuximab and monalizumab/observation and at progression.
- Health related quality of life at various time points throughout the study using the EORTC HN43 tool. [3 years]
Overall mean changes in EORTC HN43 scores in MRD+ LA-HNSCC patients from baseline (of Part A for EORTC HN43) and cross sectional comparisons including during and after cetuximab and monalizumab/observation and at progression. Overall mean changes in EORTC HN43 scores in MRD-negative LA-HNSCC patients from baseline (of Part A) and cross sectional comparisons including during first year post-definitive treatment and at progression.
- Cost effectiveness of the experimental arm vs observation at various time through the study using the EQ-5D-5L. [3 years]
Utilities Costs per life-year gained Quality adjusted life years (QAYs) Incremental cost effectiveness ratios (ICERs)
- Cost effectiveness of the experimental arm vs observation at various time through the study using the lost productivity questionnaire. [3 years]
Utilities Costs per life-year gained Quality adjusted life years (QAYs) Incremental cost effectiveness ratios (ICERs)
- Cost effectiveness of the experimental arm vs observation at various time through the study using the resource utilization assessment. [3 years]
Utilities Costs per life-year gained Quality adjusted life years (QAYs) Incremental cost effectiveness ratios (ICERs)
- Recurrence of disease or death in LA-HNSCC patients without detectable bespoke ctDNA (MRD-negative) post definitive therapy. [3 years]
DFS in the MRD-negative observational cohort.
- Comparison of bespoke ctDNA detection (MRD) as a predictive biomarker for increased risk of relapse in high risk-LA HNSCC [3 years]
Compare DFS in the MRD-negative observational cohort with DFS in the MRD+ patients under observation (Arm B in Part C).
Eligibility Criteria
Criteria
Inclusion Criteria for All Parts:
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Age ≥ 18 years at the time of screening or age of consent according to law.
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Written informed consent and any locally required authorization (e.g., data privacy) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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Weight ≥ 35 kg.
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Must have a life expectancy of at least 12 weeks.
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Histological or cytological confirmed LA-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx.
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High-risk HPV negative LA-HNSCC patients (stage III-IVB according to AJCC/UICC 8th Edition) OR high-risk HPV positive LA-HNSCC patients (stage III according to AJCC/UICC 8th Edition). HPV positive tumors (p16 positive) will be not allowed to be recruited when 12 patients have been enrolled in Part C of the trial.
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Archival tumor formalin-fixed, paraffin-embedded (FFPE) specimens for correlative biomarker studies are required (1 H&E and 10 unstained 5 microns slides). If surgery is going to be performed after signing consent, then tumor FFPE from that surgery is allowed.
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Patient is a candidate for definitive treatment: either surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation.
Inclusion Criteria for Part C
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Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definite radiation, OR definite chemoradiation)
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ECOG performance status of 0 or 1 at randomization.
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Detection of ctDNA in plasma samples collected in Part B in either:
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both samples collected at approximately week 5 (4-6) and at week 10 (8-12) OR
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only in the week 10 (8-12) sample NOTE: If ctDNA results at Week 10 are equivocal, a new sample should be collected and analyzed to confirm results within 4 weeks.
A maximum of 12 patients with HPV+ tumors will be included in this part.
- Adequate organ and marrow functions;
Hemoglobin ≥ 9 g/dL
Absolute neutrophil count ≥ 1,500 µ/L
Platelet count ≥ 100,000 µ/L
Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN is allowed in the presence of documented Gilbert's syndrome)
Alanine transaminase and Aspartate transaminase ≤ 2.5 × ULN
Albumin ≥ 3 g/dL
Serum creatinine or Calculated creatinine clearance Serum creatinine < 1.5 x ULN or CrCl ≥ 40 mL/minute
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Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception (see Section 8.1.1 for definition of females of childbearing potential and for a description of highly effective methods of contraception) from screening to 180 days after the final dose of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
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Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom with spermicide from screening to 180 days after receipt of the final dose of study treatment. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period, as described in Section 8.1.2. In addition, male subjects must refrain from sperm donation while on study and for 180 days after the final dose of study treatment.
Inclusion Criteria for Part E
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Objective radiological tumor response according to CT or MRI at 8-12 weeks after definitive therapy (surgery followed by radiation or chemoradiation, OR definitive radiation, OR definitive chemoradiation)
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No detection of ctDNA in plasma samples analysed in the week 10 (8-12) sample collected in Part B.
Exclusion Criteria:
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Histological or cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including participants with squamous cell carcinoma of unknown primary or non-squamous histologies (eg, nasopharynx, paranasal sinus or salivary gland).
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Any unresolved toxicity NCI CTCAE ≥ Grade 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with monalizumab and cetuximab may be included only after consultation with the Principal Investigator.
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Evidence of metastatic disease in staging.
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History of allogeneic organ transplantation.
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History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to cetuximab and monalizumab or any of their excipients or if the patient had red meat allergy/tick bite history.
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History of active primary immunodeficiency.
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Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], immune related diverticulitis [prior diverticulitis in the context of diverticulosis is allowed provided is not active], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
The following are exceptions to this criterion:
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Participants with vitiligo or alopecia
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Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
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Any chronic skin condition that does not require systemic therapy. Participants without active disease in the last 5 years may be included but only after consultation with the Principal Investigator
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Participants with celiac disease controlled by diet alone
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Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), or hepatitis C(HCV). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
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Patients with a known history of infection with human immunodeficiency virus (positive HIV 1/2 antibodies) are excluded. Testing in patients with no known history or no known risk factors is not required.
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Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
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History of another primary malignancy except for:
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Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence
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Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
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Adequately treated carcinoma in situ without evidence of disease
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Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤ T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention
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Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 500 ms calculated from 3 ECGs.
Prior/Concomitant Therapy
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Any concurrent anticancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
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No prior head and neck irradiation.
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Prior cetuximab or monalizumab therapy.
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Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion:
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Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
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Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
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Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
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Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention.
Prior/Concurrent Clinical Study Experience
- Participation in another clinical study with an investigational product administered in the last 28 days prior to randomization or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
Other Exclusions
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Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
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For women only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
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Females who are pregnant, lactating, or intend to become pregnant during their participation in the study.
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Subjects who are involuntarily incarcerated or are unable to willingly provide consent or are unable to comply with the protocol procedures.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University Health Network, Toronto
- AstraZeneca
- Eli Lilly and Company
Investigators
- Principal Investigator: Lillian Siu, MD, Princess Margaret Cancer Centre
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MERIDIAN