This study has been transitioned to CTIS with ID 2023-508342-17-00 check the CTIS register for the current data. Primary Objective• To assess the effect of ALX148 + pembrolizumab + 5FU + platinum on 12-month overall survival (OS) rate and objective…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Head and neck squamous cell carcinoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
• 12-month overall survival (OS) rate of ALX148 + pembrolizumab + 5FU +
platinum.
• Objective response rate of ALX148 + pembrolizumab + 5FU + platinum (ORR; CR
or PR using the Response Evaluation Criteria in Solid Tumors
[RECIST] version 1.1).
Secondary outcome
Secondary Endpoints
• Disease control rate (DCR), duration of response (DOR), time to tumor
progression (TTP).
• Progression-free survival (PFS), and overall survival (OS).
• Adverse Events as characterized by type, frequency, severity (as graded by
National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to
study therapy.
• Laboratory abnormalities as characterized by type, frequency, severity (as
graded by NCI CTCAE v. 5.0) and timing.
• Pharmacokinetic parameters of ALX148 such as Cmax, Tmax, AUC, CL, and t1/2 as
data permit.
• Immunogenicity; Human serum ADA (i.e., anti-ALX148 antibody) samples will be
analyzed for the presence or absence of anti-ALX148
antibodies.
Background summary
The CD47 - SIRPα pathway is implicated in the regulation of myeloid cell
functions and pathologic immune evasion by cancer cells. CD47 is a widely
expressed cell surface protein that functions as a marker of self. CD47
provides a *don*t eat me* signal that distinguishes viable/healthy cells from
apoptotic/abnormal cells (Oldenborg, 2013). SIRPα is the CD47 receptor on
macrophages. CD47 binding to this receptor inhibits phagocytosis of healthy
cells, while cells displaying low levels of CD47 are susceptible to
macrophage-mediated destruction (Khandelwal et al, 2007; Oldenborg et al,
2000). Tumor cells overexpress CD47 to evade the macrophage component of immune
surveillance. Abundant CD47 expression has been observed in a wide variety of
hematologic and solid tumors. In some reports, elevated CD47 mRNA expression
may correlate with poor survival in individuals with cancer (Willingham et al,
2012; Chao et al, 2010; Yoshida et al, 2015). Similar to the adaptive
anti-tumor activity of T cells, the innate anti-tumor activity of macrophages
is regulated via a balance between activating signals (*eat me*) and the
inhibitory signals (*don*t eat me*). Phagocytosis requires both the activation
of "eat me" signals and the disruption of "don't eat me" signals. Neither
component alone is sufficient to trigger maximal phagocytic reaction against
tumor cells. CD47 provides a fundamental *don*t eat me* signal through its
interaction with SIRPα on macrophages. The pro-phagocytic "eat me" signal can
be provided to the same macrophages by binding to their activating Fc gamma
receptors. In this way, the CD47 - SIRPα interaction is considered to be a
checkpoint for innate immunity similar to PD-L1 / PD-1 for adaptive immunity.
CD47 blockers with an active Fc domain, such as CD47 blocking antibodies or
CD47 blocking fusion proteins linked to an active Fc domain, are able to
provide both components required for tumor cell phagocytosis. The
pro-phagocytic *eat me* signal is provided through the interaction of their Fc
domain with the Fc gamma receptors. Although such CD47 blockers have been shown
to increase phagocytosis of cancer cells in nonclinical studies, they have also
been associated with on-target toxicities such as anemia, neutropenia, and/or
thrombocytopenia in clinical studies (Branimir et al, 2016; Ansell et al,
2016). Anemia has also been seen in animal studies with CD47 blocking
antibodies (Liu et al, 2015a). ALX148 is a high affinity engineered fusion
protein containing the N-terminal D1 domain of SIRPα genetically linked to a
modified Fc domain from human IgG1. ALX148 is a CD47 blocker specifically
designed to avoid such potential on-target toxicity of CD47-expressing blood
cells by containing an inactive Fc domain. It is intended to be used in
combination with targeted immunotherapeutic agents for the treatment of adult
patients with advanced malignancy. ALX148 is designed specifically to bind to
CD47 and block the *don*t eat me* signal, however, it lacks an active Fc
domain. Thus, it does not interact with Fc gamma receptors and is not expected
to activate phagocytosis by itself. The second required "eat me" signal can be
independently and selectively provided by anti-cancer therapeutics that contain
an active Fc, such as Herceptin® (trastuzumab), Erbitux® (cetuximab) or
Rituxan® (rituximab). By separating the two signals, it is possible to
selectively direct macrophages to cancer cells and spare normal cells. Blocking
the CD47 pathway may also enhance the adaptive immune response, leading to
increased anti-tumor activity by multiple mechanisms. As suggested by
preclinical studies, CD47 blockade may prime or boost tumor-specific CD8+
effector T cells by bridging innate immune dendritic cell (DC) activation
and/or enhancing the phagocytosis and enabling processing and presentation of
tumor antigens (Tseng et al, 2013; Soto-Pantoja et al. 2014; Liu et al. 2015b;
Sockolosky et al. 2016). Additionally, by modulating the phagocytic activity of
tumor associated macrophages (TAMs), CD47 blockade may result in the
reprogramming of TAMs to lessen the inhibition of cytotoxic T cell lymphocytes.
CD47 blockade may even directly augment activation of CTLs and inhibit T
regulatory cells (Avice et al., 2000; Van et al 2008). Thus, ALX148, through
its blockade of CD47, may augment anti-tumor adaptive immunity in combination
with other cancer immunotherapies, including anti-PD-1 and anti-PD-L1
inhibitors such as Keytruda® (pembrolizumab), Opdivo® (nivolumab), & Tecentriq®
(atezolizumab). Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4)
monoclonal antibody (mAb) with high specificity of binding to the programmed
cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed
cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based
on preclinical in vitro data, pembrolizumab has high affinity and potent
receptor blocking activity for PD 1. Pembrolizumab has an acceptable
preclinical safety profile and is in clinical development as an intravenous
(IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is
indicated for the treatment of patients across a number of indications. As a
consequence, the PD 1/PD-L1 pathway is an attractive target for therapeutic
intervention in metastatic or unresectable recurrent HNSCC and an attractive
combination partner for an anti-CD47 agent such as ALX148. Patients with solid
tumor malignancies for which targeted immunotherapy treatment is indicated,
such as recurrent, unresectable or metastatic HNSCC, may benefit from a
combination approach with ALX148. HNSCC of the oropharynx is the 11th most
common cancer worldwide and represents 3% of all new cancer cases in the United
States, with an estimated 10,860 cancer related deaths to occur in 2019
(National Cancer Institute SEER 2019; World Health Organization 2019). For
patients whose cancer has metastasized, the 5-year survival rate is 39.1%
(National Cancer Institute SEER 2019). In the paradigm-shifting KEYNOTE 48
study, pembrolizumab in combination with 5FU and platinum therapy was shown to
improve patients* overall survival compared with cetuximab plus 5FU and
platinum therapy with a HR 0.65 (95% CI 0.53-0.80, P< .0001) and median OS of
13.6 vs 10.4 months in patients with CPS (Combined Positive Score ) >=1 thus
establishing a new standard of care for patients with newly
recurring/metastatic HNSCC (Burtness et al. 2019). In addition, pembrolizumab
as a single agent improved overall survival vs the standard of care regimen of
cetuximab, platinum and 5FU, with a median overall survival of 11.5 vs 10.7
months, respectively (HR = 0.83, 95% CI = 0.70-0.99, P = .0199). Lastly,
although the overall response rate for single-agent pembrolizumab was
noticeably lower than that for cetuximab/chemotherapy (16.9% vs 36.0%), the
median duration of response for pembrolizumab alone was substantially longer
(22.6 vs 4.5 months), suggesting that single-agent pembrolizumab is also an
efficacious option for a subset of patients with R/M HNSCC, leading to FDA
approval of pembrolizumab alone for patients with a CPS of at least 1. Despite
these advances, patients who have not yet been treated for recurrent/metastatic
HNSCC still have a median overall survival of only approximately 1 year and are
in need of novel combination treatment options that do not significantly
increase the toxicity of the currently available regimens. As reported in
preliminary clinical results (Chow et al. 2020) in checkpoint nai*ve patients,
and non-clinical studies (Kauder et al. 2018), coupling ALX148 with a
checkpoint inhibitor demonstrates clinical benefit, and also provides a strong
rationale for combining this doublet with standard of care chemotherapy
regimens in patients with first-line metastatic or unresectable, recurrent
HNSCC. Preliminary
Study objective
This study has been transitioned to CTIS with ID 2023-508342-17-00 check the CTIS register for the current data.
Primary Objective
• To assess the effect of ALX148 + pembrolizumab + 5FU + platinum on 12-month
overall survival (OS) rate and objective response rate (ORR)
in patients with metastatic or unresectable, recurrent HNSCC who have not yet
been treated for their advanced disease.
Secondary Objectives
• To assess secondary measures of efficacy for ALX148 administered in
combination with pembrolizumab + 5FU + platinum and for
pembrolizumab + 5FU + platinum.
• To assess the safety and tolerability of ALX148 administered in combination
with pembrolizumab + 5FU + platinum and for
pembrolizumab + 5FU + platinum (including for patients in the safety lead-in
cohort.
Study design
This is a non-comparative phase 2 open-label, multi-center study of the
anti-tumor efficacy of ALX148 + pembrolizumab + chemo versus pembrolizumab +
chemo in patients with metastatic or unresectable, recurrent HNSCC who have not
yet been treated for their advanced disease HNSCC.
The study comprises of an initial safety lead-in followed by a randomized
portion. At least six patients will be enrolled into the safety lead-in. These
lead-in patients will be observed for toxicity for the first 21 days (Cycle 1).
Once review of the safety lead-in is complete a non-comparative
randomized phase 2 Simon minimax study design will be used to evaluate the
anti-cancer activity of ALX148 + pembrolizumab + chemotherapy versus
pembrolizumab + chemotherapy for the treatment of patients with metastatic or
with unresectable, recurrent HNSCC who have not yet been treated for their
advanced disease. The control arm of pembrolizumab + chemo will serve as a
validation of historical controls rather than a direct comparator. The study
will randomize approximately 106 patients after the safety lead-in cohort. A
total of 71 patients will be randomized in the experimental arm and 35 patients
will be randomized to the control arm, using a 2:1 allocation ratio.
Intervention
Patients will be administered ALX148 45 mg/kg Q3W in a 21-day cycle with
pembrolizumab dosed at 200 mg IV infusion over 30 minutes every 3 weeks for up
to a maximum of 35 cycles (approximately 24 months), carboplatin dosed at AUC 5
mg/ml/min as a 60 min infusion Day 1 Q3W x6, OR cisplatin dosed at 100 mg/m2 as
a 60 min infusion Day 1 Q3W x 6 (Investigator*s choice), and 5-FU dosed at 1000
mg/m2/day continuous infusion Days 1, 2, 3, 4 Q3W x 6. Patients who do not have
disease progression and who continue to meet retreatment criteria may continue
to receive ALX148. Pembrolizumab may continue up to a maximum of 35 cycles
(approximately 24 months) in patients without disease progression. Carboplatin,
cisplatin, and 5FU are administered per label for 6 cycles.
The patients in the safety lead-in will receive ALX148 + pembrolizumab +
chemotherapy and will undergo additional PK sampling during cycles 1 and 3 with
the goal of obtaining a dense PK sample set. The patients on ALX148 +
pembrolizumab + chemo in the randomized portion of the study will undergo
sparse PK sampling pre- and post-infusion during the first 6 cycles of
treatment.
Study burden and risks
The burden and risk mainly consist out of extra time spent in comparison to
standard treatment and side effects, and the risks of
medical evaluation, including venapuncture, biopsy and MRI/CT scans.
Allerton Avenue 323
South San Francisco, CA 94080
US
Allerton Avenue 323
South San Francisco, CA 94080
US
Listed location countries
Age
Inclusion criteria
1. Patients with metastatic or unresectable, recurrent head and neck squamous
cell carcinoma (HNSCC) who have not received prior systemic therapy for their
advanced disease. PD-L1 status as defined by combined positive score (CPS) and
as assessed by an FDA-approved test using the 22C3 antibody must be available.
• Patients cannot have received prior systemic therapy for the treatment of
metastatic or recurrent disease. • Patients can have received prior systemic
therapy for the treatment of locoregionally advanced disease if it was
completed more than 6 months prior to signing informed consent. 2. Patients
must have at least one measurable lesion as defined by RECIST version 1.1. 3.
Adequate bone marrow function. 4. Adequate renal function (estimated creatinine
clearance by Cockroft-Gault equation of >= 60 mL/min.). 5. Adequate liver
function. 6. Age >=18 years, except in regions in which the minimum age for
subject participation is >18 years. 7. INR or PT and PTT <1.5X ULN unless
participant is receiving anticoagulant therapy as long as PT or aPTT is within
therapeutic range of intended use of anticoagulants. 8. ECOG performance status
0 or 1. 9. Participants with oropharyngeal carcinoma must have available
results from testing of human papillomavirus (HPV) (p16) status. 10.
Participants must have recovered from all AEs due to previous therapies,
procedures, and surgeries to baseline or <=Grade 1 per NCI CTCAE v. 5.0 except
for AEs not constituting a safety risk by Investigator judgment. Participants
with <=Grade 2 neuropathy may be eligible. 11. Available core or incisional
biopsy sample prior to study entry, preferably taken after the most recent
therapy for HNSCC, for central confirmation of PD-L1 CPS and evaluation of
other biomarkers. Fine needle aspirates are not acceptable. 12. Serum pregnancy
test (for females of childbearing potential) negative at screening. 13. Male
and female patients of childbearing potential must agree to use a highly
effective method of contraception throughout the study and for at least 120
days after the last dose of assigned treatment and at least 6 months (or longer
if required by local regulation) after the last dose of chemotherapy, whichever
is later. 14. Evidence of a personally signed and dated informed consent
document, from a patient with the capacity to consent for themselves or from a
legal representative, indicating that the patient or legal representative has
been informed of all pertinent aspects of the study before any study-specific
activity is performed. 15. Patients who are willing and able to comply with
scheduled visits, treatment plans, laboratory tests, and other procedures.
Exclusion criteria
1. Patients with disease suitable for local therapy with curative intent.
2. Patients with progressive disease within 6 months of completion of
curatively intended systemic therapy for the treatment of locoregionally
advanced HNSCC.
3. Patients with nasopharyngeal carcinoma (NPC).
4. Patients with known symptomatic CNS metastases requiring steroids or with
leptomeningeal disease.
5. Has a history of (non-infectious) pneumonitis / interstitial lung disease
that required steroids or has current pneumonitis / interstitial lung disease.
6. Prior radiotherapy within 2 weeks of start of study treatment.
7. Prior treatment with any anti-CD47 or anti-SIRPα agent.
8. Prior treatment with a PD-1 or PD-L1, or anti PD L2 agent or with an agent
directed to another stimulatory or co-inhibitory T cell receptor
(e.g., CTLA-4, OX 40, CD137).
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior the
first dose of study drug.
10. Has a diagnosis of complete dihydropyrimidine dehydrogenase (DPD)
deficiency. Testing for DPD status is required for sites/regions in which
such testing is standard of care (such as in the United Kingdom).
11. Has an active autoimmune disease that has required systemic treatment in
past 2 years.
12. History of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or
hemolytic transfusion reaction.
13. Patients with intolerance to or who have had a severe allergic or
anaphylactic reaction to antibodies or infused therapeutic proteins or
patients who have had a severe allergic or anaphylactic reaction to any of the
substances included in the study drugs.
14. Patients with significant hearing impairment.
15. Any experimental antibodies or live vaccines in the last 30 days prior to
the first dose of study drug.
16. Patients with active, uncontrolled, clinically significant bacterial,
fungal, or viral infection.
17. Has an active infection requiring systemic therapy.
18. Has had an allogeneic tissue/solid organ transplant.
19. Any of the following in the previous 6 months: myocardial infarction,
unstable angina, coronary/peripheral artery bypass graft, NYHA Class II
or greater congestive heart failure, cerebrovascular accident, or transient
ischemic attack, deep venous thrombosis, arterial thrombosis,
symptomatic pulmonary embolism, or any other significant thromboembolism. Any
major surgery within 28 days prior to enrollment.
20. Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4
weeks prior to the first dose of study treatment.
21. Diagnosis of any other malignancy within the last 3 years prior to
enrollment except for adequately treated non-melanomatous skin cancer, or
carcinoma in situ
that have undergone potentially curative therapy.
22. Other severe acute or chronic medical or psychiatric condition.
23. Patients who are pregnant or breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508342-17-00 |
| EudraCT | EUCTR2020-004662-19-NL |
| ClinicalTrials.gov | NCT04675294,IND139180 |
| CCMO | NL76478.042.21 |