Sub-study APhase 1b:To assess the DLT rate and estimate the MTD of sasanlimab in combination with encorafenib and binimetinib to determine the RP2D for the combination. Phase 2:To assess the durable ORR of sasanlimab in combination with encorafenib…
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Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Sub-study A
Phase 1b:
DLTs during the DLT observation period.
Phase 2:
Durable OR, defined as confirmed CR or PR lasting for at least 10*months from
the date of first CR or PR, as assessed by the investigator using RECIST v1.1.
Sub-study B
Phase 1b:
DLTs during the DLT observation period.
Phase 2:
OR, defined as confirmed CR or PR, as assessed by the investigator using RECIST
v1.1.
Secondary outcome
Sub-study A
Phase 1b:
AEs graded according to the NCI-CTCAE v5.0 and changes in clinical laboratory
parameters.
Durable OR and OR as assessed by the investigator using RECIST v1.1.
PK parameters of sasanlimab, encorafenib, binimetinib and applicable
metabolites (ie, Ctrough) when administered in combination, as data permit.
ADA and NAb (ie, incidence) against sasanlimab, as data permit.
Phase 2:
OR, DR, TTR, PFS by investigator assessment using RECIST v1.1, and OS.
AEs graded according to the NCI-CTCAE v5.0 and changes in clinical laboratory
parameters.
PK parameters of sasanlimab, encorafenib, binimetinib, and applicable
metabolites (ie, Ctrough) when administered in combination, as data permit.
ADA and NAb (ie, incidence) against sasanlimab, as data permit.
OR by PD-L1 expression in baseline tumor samples.
Health-related quality of life as measured by EORTC QLQ-C30/LC13
Sub-study B
Phase 1b:
AEs graded according to the NCI-CTCAE v5.0 and changes in clinical laboratory
test parameters.
OR, DR, TTR, PFS by investigator assessment using RECIST v1.1.
PK parameters (Cmax, Ctrough) of sasanlimab, axitinib, and SEA-TGT, as data
permit.
ADA (ie, incidence) against sasanlimab, as data permit.
ADA (ie, incidence) against SEA-TGT, as data permit.
Phase 2:
DR, TTR, PFS by investigator assessment using RECIST v1.1, and OS.
AEs graded according to the NCI-CTCAE v5.0 and changes in clinical laboratory
test parameters.
PK parameters (Cmax, Ctrough) of sasanlimab, axitinib, and SEA-TGT, as data
permit.
ADA against sasanlimab, as data permit.
ADA against SEA-TGT, as data permit.
OR by PD-L1 expression in available tumor tissue (archival or de novo, primary
or metastatic).
Background summary
Study B8011011 is a master protocol for the treatment of participants with
locally advanced/metastatic (Stage IIIBIV) NSCLC, incorporating an anti-PD1 mAb
(sasanlimab) as the backbone therapy for combinations with different
molecularly targeted agents. B8011011 is primarily designed as an exploratory
study.
NSCLC is a disease which is responsive to immune-checkpoint inhibition. In the
first-line advanced NSCLC setting, PD1/PDL1 inhibitors as single agents are
effective in tumors with strong antitumor T*cell activity which has been
down-modulated by tumor-associated PDL1 expression. High PDL1 expression is
observed in approximately 50% of advanced NSCLC PDL1-positive cases. For the
majority of patients with NSCLC, the use of PD1/PDL1 inhibitors as single
agents is insufficient to control disease progression.
For patients with advanced NSCLC in the first-line setting, combinations of
PD1/PDL1 agents with chemotherapy are the most common standard-of-care regimens
for those patients who can tolerate chemotherapy and who do not have known
targetable aberrations. Upon progression, patients treated with
chemotherapy/PD1/PDL1 combinations have limited effective treatment options and
may be treated with other chemotherapy-containing regimens, which are not
highly effective in providing participants with long-term benefit and for
docetaxel, the product label contains a black-box warning for severe toxicities.
Mechanisms of resistance to PD1/PDL1 therapies have been proposed to include
b2microglobulin/MHC Class I down-modulation, insufficient amount of tumor
antigens recognizable by T cells, and upregulation of alternative immune
suppressive mechanisms (eg, TGFb pathway upregulation, alternative immune
checkpoints, PTEN loss).
Combinations of targeted therapies having the capability of stimulating
anti-tumor immunity with PD1/PDL1 agents have shown improved clinical activity
compared with targeted agents alone. Examples include triplet combinations
that show activity in patients with metastatic melanoma. Triplet combinations
of PD1/PDL1 inhibitors with a BRAF inhibitor and MEK inhibitor have shown
activity, including a)*pembrolizumab with dabrafenib/trametinib or
b)*atezolizumab with vemurafenib/cobimetinib. In these clinical studies, the
addition of the PD1/PDL1 inhibitor resulted in an improvement in the durability
of responses and trends toward improvement in PFS and OS. ORR was comparable
between the targeted agents alone and the triplets.
Combinations of sasanlimab with targeted therapy are designed to leverage the
relatively rapid reduction in tumor burden possible with targeted therapy and
the relatively prolonged tumor control produced by an effective immune
response. This hypothesis predicts that the effect of the targeted therapy
will be reflected in the ORR, whereas the effect of sasanlimab will be manifest
as extensions of DR, PFS, and OS.
It has been observed in multiple clinical trials of a PD1/PDL1 agent with other
therapies in NSCLC that due to the kinetics of immune-associated anti-tumor
activity, neither the ORR nor mPFS are reliable predictors of OS. In fact,
what has been observed with these combinations is that a greater durability of
disease control in the intent-to-treat patient population and high maximum
depth of the anti-tumor response correlates with an improvement in OS.
Accordingly, durable response will be either a primary endpoint or coprimary
endpoint with OR, depending on the design of each substudy.
To summarize, the central goal of this study is to identify combinations that
lead to improved anti-tumor activity by activating and sustaining anti-tumor
immunity.
Study objective
Sub-study A
Phase 1b:
To assess the DLT rate and estimate the MTD of sasanlimab in combination with
encorafenib and binimetinib to determine the RP2D for the combination.
Phase 2:
To assess the durable ORR of sasanlimab in combination with encorafenib and
binimetinib.
Sub-study B
Phase 1b:
To assess the DLT rate and estimate the MTD of sasanlimab in combination with
axitinib and SEA-TGT to determine the RP2D for the combination.
Phase 2:
To assess the ORR of sasanlimab in combination with axitinib and SEA-TGT.
Study design
Overall Design
This is a prospective, open-label, multi-center, parallel group, Phase*1b/2
umbrella study to evaluate safety, efficacy, pharmacokinetics, and/or
pharmacodynamics of sasanlimab in combination with targeted agents that
increase anti-tumor immunity and activity in adult participants with locally
advanced or metastatic NSCLC. Each sub-study may be conducted in parallel, as
new agents are included to begin a substudy within the framework of the master
protocol. Each sub-study will specify the treatment setting. Participants
will receive study interventions*until permanent treatment discontinuation
criteria are met.
The combination arms will be assessed individually in 2 parts:
A Phase*1b part to evaluate the safety of the combination and select an RP2D
dose level for the combination.
A Phase*2 part to evaluate the activity and further evaluate the safety of the
RP2D from the Phase*1b part in pre-specified participant populations.
Phase 1b Design:
The sasanlimab dose will remain fixed (at either 300*mg SC Q4W or 225 mg SC
Q3W) for all cohorts in the Phase*1b part of each substudy.
Guidance for the Phase*1b dosing (dose level to be evaluated in the next
cohort) and enrollment decisions (number of participants to be enrolled in the
next cohort) will be based on methods described for each substudy.
Phase 2 Design:
Once the Phase*1b is completed for a sub-study and the combination RP2D has
been determined, Phase*2 for the sub-study may be initiated to further evaluate
the safety and antitumor activity.
Intervention
Sasanlimab SC (either 300 mg Q4W or 225 mg Q3W) will be administered in all
substudies (Phase 1b).
In Sub-Study A the investigational products administered will be sasanlimab,
encorafenib, and binimetinib as a triplet therapy.
In Sub-Study B the investigational products administered will be sasanlimab,
axatinib, and SEA-TGT as a triplet therapy.
Phase 2 Dose Levels:
RP2D/MTD of sasanlimab + other study drugs
Study burden and risks
The benefit risk relationship has been carefully considered in the planning of
this study.
Based on data from Study B8011001, there is significant clinical benefit in
terms of OR and disease control for participants with advanced/metastatic solid
tumors treated with single-agent sasanlimab. These results are consistent with
the ORR and DCR in the same tumor types reported for other agents of the same
class. Sasanlimab is well tolerated and with a low frequency of
treatment-related SAEs.
The clinical safety data available to date with singleagent sasanlimab suggest
an acceptable safety profile with most of the observed AEs in line with those
expected in patients with advanced solid tumors or with similar class effects
of mAbs blocking the PD1/PDL1 axis.
Immune-related AEs have been identified as important risks for sasanlimab and
risk mitigation measures have been implemented in all ongoing clinical studies,
including this study. These measures include guidelines for treatment
interruption and discontinuation in case of toxicities, and guidelines for
steroid treatment implementation. In the same study sasanlimab has shown
evidence of clinical activity aligned to other antiPD1/PD-L1 single agents in
participants with advanced/metastatic NSCLC.
The fact that PD-1 antagonists are known to be combinable with many other
agents is also important to consider. There are exceptional cases where
combinations were not tolerated and combinations with agents of the same class
will not be conducted in this study. Agents combined with sasanlimab will have
a singleagent MTD and/or a RP2D determined in other studies as a basis for the
design of the Phase 1b safety cohorts in this study. A safe dose level for
each combination will be determined in Phase*1b of this study before proceeding
to a Phase 2 expansion cohort.
Based on the above considerations, the benefit/risk assessment for the
initiation of Phase 1b safety cohorts for combinations with other agents is
favorable.
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Age
Inclusion criteria
Phase 1b and Phase 2 for All Sub Studies:
Age and Sex:
• Male or female participants age >=18 years at Screening (except in Japan,
where participants must be >=20 years).
• Male and female participants must agree to contraceptive use
• Female participants of childbearing potential must have negative serum
pregnancy or urine pregnancy test at Screening.
Type of Participant and Disease Characteristics:
• Documented histologically or cytologically confirmed locally
advanced/metastatic (Stage IIIB IV) NSCLC, per AJCC/ International Union for
Cancer Control TNM system, 7th edition. For Stage IIIB disease relapse during
treatment or within 6 months following adjuvant therapy will be considered
metastatic disease. In addition, for Stage IIIB, must not be amenable for
definitive therapy (eg, surgery or chemoradiation).
• At least 1 measurable lesion per RECIST v1.1 at Screening.
• ECOG Performance Status 0 or 1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE
Grade <=1 unless otherwise specified
• Life expectancy >=3 months as assessed by the investigator for previously
treated participants or >=12 months for first-line untreated participants.
• Adequate bone marrow function (without hematopoietic growth factor or
transfusion support within 14 days prior to first dose of study intervention),
including:
a. Absolute neutrophil count >=1500/mm3 or >=1.5 × 109/L;
b. Platelets >=100,000/mm3 or >=100 × 109/L;
c. Hemoglobin >=9 g/dL (may have been transfused).
• Adequate renal function, defined by:
Estimated creatinine clearance >=30 mL/min according to the Cockcroft-Gault
formula or by 24 hour urine collection for creatinine clearance, or according
to local institutional standard method.
• Adequate liver function, including:
a. Total serum bilirubin <=1.5 × ULN unless the participant has documented
Gilbert syndrome;
b. AST and ALT <=2.5 × ULN; <=5.0 × ULN if there is liver involvement by the
tumor;
c. Alkaline phosphatase <=2.5 × ULN (<=5 × ULN in case of bone metastasis).
• Additional inclusion criteria for sub-study A are listed in Protocol section
12.5.1
• Additional inclusion criteria for sub-study B are listed in Protocol section
13.5.1
Exclusion criteria
Phase 1b and Phase 2 for All Sub Studies:
Medical Conditions:
• Active or prior autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Participants with diabetes type I, vitiligo,
psoriasis, or hypothyroid or hyperthyroid disease not requiring
immunosuppressive treatment are eligible.
• Previous Grade >=3 irAE; or unresolved irAEs prior to first dose of study
intervention.
• Active, non-infectious pneumonitis, pulmonary fibrosis, or known history of
immune-mediated pneumonitis.
• Active infection requiring systemic therapy.
• Clinically significant cardiovascular diseases, including any of the
following:
a) History of acute myocardial infarction, acute coronary syndromes (including
unstable angina, coronary artery bypass graft, coronary angioplasty or stenting)
<=6 months prior to start of study treatment;
b) Congestive heart failure requiring treatment (New York Heart Association
Class >=2);
c) Uncontrolled hypertension defined as persistent systolic blood pressure >=150
mmHg or diastolic blood pressure >=100 mmHg despite optimal therapy;
d) History or presence of clinically significant or uncontrolled sustained
cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled
paroxysmal supraventricular tachycardia);
e) History of thromboembolic or cerebrovascular events <=3 months prior to the
first dose of study treatment. Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (ie, massive or sub
massive) deep vein thrombosis or pulmonary emboli.
Note: Participants with either deep vein thrombosis or pulmonary emboli that do
not result in hemodynamic instability are allowed to enroll as long as they are
stable, asymptomatic and on stable anticoagulants for at least 2 weeks.
Note: Participants with thromboembolic events related to indwelling catheters
or other procedures may be enrolled.
• Other malignancy within 2 years prior to the first dose of study
intervention, except for adequately treated basal cell or squamous cell skin
cancer, or carcinoma in situ of the breast or of the cervix, or low-grade
(Gleason 6 or below) prostate cancer on surveillance without any plans for
treatment intervention (eg, surgery, radiation, or castration) or other
concurrent malignancy investigator feels has a very low likelihood to become
metastatic.
• Clinically significant multiple or severe drug allergies, intolerance to
topical corticosteroids, or severe post-treatment hypersensitivity reactions
(including, but not limited to, erythema multiforme major, linear
immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative
dermatitis.
• Symptomatic brain metastasis: participants previously treated for this
condition or untreated with brain metastases <10 mm without associated
edema, who are asymptomatic in the absence of corticosteroid therapy are
allowed.
• Leptomeningeal disease.
• Known history of acute or chronic pancreatitis.
• Concurrent neuromuscular disorder that is associated with the potential of
elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic
lateral sclerosis, spinal muscular atrophy).
• Other medical or psychiatric condition including recent (within the past
year) or active suicidal ideation/behavior or laboratory abnormality that may
increase the risk of study participation or, in the investigator*s judgment,
make the participant inappropriate for the study.
• Participants with active, uncontrolled bacterial, fungal, or viral infection,
including HBV, HCV, or known HIV infection. If HIV infection status is unknown,
testing for HIV must be performed at sites where mandated locally.
Prior/Concomitant Therapy:
• Live attenuated vaccines within 4 weeks prior to first dose of study
intervention and while on study treatment.
• Major surgery or received radiation therapy within 2 weeks prior to first
dose of study intervention.
Other Exclusions:
• Investigator site staff or Pfizer employees directly involved in the conduct
of the study, site staff otherwise supervised by the investigator, and their
respective family members.
Additional exclusion criteria for sub-study A criteria are detailed in Protocol
section 12.5.2.
Additional exclusion criteria for sub-study B criteria are detailed in Protocol
section 13.5.2.
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 |
|---|---|
| EudraCT | EUCTR2020-002829-28-NL |
| ClinicalTrials.gov | NCT04585815 |
| CCMO | NL79228.056.21 |