This study has been transitioned to CTIS with ID 2023-508067-70-00 check the CTIS register for the current data. The primary objective is to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of BMS…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Patients with Advanced Solid Tumors (see protocol for tumor types)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
The primary endpoint of this Phase 1/2a study is safety as measured by the rate
of AEs, serious adverse events (SAEs), deaths, and laboratory abnormalities,
assessed during treatment and for up to for 135 days after the last treatment.
All subjects who receive at least one dose of BMS-986016 or nivolumab will be
analyzed for safety.
Secondary outcome
Secondary Endpoints:
Efficacy: The best overall response (BOR), objective response rate (ORR, i.e.,
CR + PR), disease control rate (DCR) at 12 weeks, duration of response (DOR),
and progression-free survival (PFS) will be assessed based on RECIST v1.1
criteria. Landmark PFS rates at pre-specified time points, e.g., 24 weeks, will
be assessed.
Pharmacokinetics: Select BMS-986016 PK parameters, such as Cmax, Ctrough, Tmax,
AUC (TAU), CLT, and AI, will be assessed from concentration-time data during
Cycle 1 and Cycle 3.
Immunogenicity: The proportion of subjects who develop specific ADA to either
BMS-986016 or Nivolumab will be measured during treatment and for up to 135
days after their last treatment in post-treatment follow-up.
ECG: In Parts A and B, QTc will be assessed by a central reader for ECG
collected at follow-up visit 1, as well as on Day 1 of Cycle 1 and Cycle 3 at
the pre-dose and 4-hour post-dose time points.
Exploratory Endpoints:
Biomarkers: Biomarker endpoints from peripheral blood may include, but not
limited to, measures such as levels of soluble factors, as well
characterization by immunophenotyping, at each scheduled timepoint.
Biomarker endpoints from tumor biopsies may include but will not be limited to
measures such as level of immune cell infiltration, somatic mutational load,
expression of IFN response genes, functional status and diversity of T cell
receptor repertoire, and expression of lymphocyte activation gene 3 (LAG-3),
major histocompatibility complex (MHC) class II, PD-1, and PD-L1.
Pharmacokinetics: PK parameters will include nivolumab concentration-time data
at select trough (Ctrough) and end-of-infusion (EOI) timepoints based on
measurements collected for up to 135 days during the post-treatment follow-up.
Efficacy: Landmark overall survival will be an exploratory efficacy endpoint in
subjects treated with BMS-986016 alone and in combination with nivolumab.
Background summary
Background of Nivolumab (BMS 936558) and BMS-986016 and explanation of the
study design
The study involves two drugs, nivolumab and a lymphocyte activation gene-3
(LAG3) monoclonal antibody:
• Nivolumab is a fully human monoclonal antibody that binds to PD-1 with
nanomolar affinity and a high degree of specificity, thus precluding binding of
PD-1 to its ligands PD-L1 and PD-L2. Results from Phase 1 and 2 clinical trials
have demonstrated complete response (CR), partial response (PR), and mixed
response in patients with advanced solid tumors, including colorectal cancer,
lung cancer, melanoma, and renal cell carcinoma (RCC), among others.
• BMS-986016 (anti-LAG-3) is an investigational product, which is thought to
work by attaching to and blocking a molecule called Lymphocyte Activation
Gene-3 (LAG-3). LAG-3 is a protein that is that is expressed on the cell
surface of activated CD4+ and CD8+ T cells and subsets of NK and dendritic
cells. It has been reported that LAG-3 plays an important role in promoting
regulatory T cell (Treg) activity and in negatively regulating T cell
activation and proliferation. Antibodies that block LAG-3 can potentially
prevent LAG-3 from shutting down the immune system, thus allowing it to
recognize and help your body destroy the cancer cells.
There is a growing amount of evidence in the literature which supports the
strong synergy between the PD-1 and LAG- 3 inhibitory pathways that seems to
mediate tolerance to both self and tumor antigens, and dual knock-out mice show
markedly increased survival from and clearance of multiple transplantable
tumors. Combined inhibition of T cell checkpoint molecules, such as CTLA-4,
PD-1, and LAG-3, have led to the discovery of one of the key signature
molecules associated with T cell exhaustion, the negative T cell regulator,
LAG-3, and to the development of the
antagonistic LAG-3 antibody, BMS-986016.
An initial evaluation of the safety, tolerability, pharmacokinetics (PK), and
pharmacodynamics will be conducted with an escalation arm of BMS-986016
monotherapy. It is proposed that this antibody should be considered for the
treatment of multiple malignancies in combination with nivolumab (an anti-PD-1
antibody) as a T cell-core therapy with the aim
to:
•increase the number, type, and duration of responses in tumors known to
respond to T cell checkpoint inhibitors*
•rescue an adaptive response where patients are refractory to T cell checkpoint
inhibitors and have progressed
clinically* and/or
•enhance the antitumor immunity in malignancies associated with chronic viral
infections (e.g., HPV, EBV, HCC, HBV,
etc).
The Netherlands will be planning to join the study at the point of part C. In
these cohorts the drug combinations are given twice weekly for a maximum of 96
weeks, depending on response to treatment. CA224020 currently consists of 4
parts. Part A and Part B consist of a 3 + 3 + 3 dose escalation design with
BMS-986016 administered as a single agent (Part A) or in combination as with
nivolumab as sequential infusion (Part B) in subjects with advanced solid
tumors.
Part C consists of expansion cohorts of approximately 25-40 subjects each in
disease-restricted populations (and further expansion of up to approximately
90-120 subjects in selected cohorts based upon safety and efficacy profiles),
with BMS-986016 administered in combination with nivolumab as sequential
infusions. The design of the study in part B provides a simple dose algorithm,
designed to accurately find the best dose whilst minimising the number of
patients being treated at doses that may not have an affect on the cancer.
The starting doses for Part B were selected based on all nonclinical data
available from studies of the combination and BMS-986016 monotherapy and on
emerging clinical safety and pharmacokinetic data from Part A monotherapy.
The dosing for subjects in part C will be agreed upon by investigators and with
the sponsor based on dosing shown to be safe in part B. In part B and C, the
sequential infusion of both drugs will start with nivolumab administrations
first followed by infusion of BMS-986016.
This study will utilize a flat dose escalation and expansion since it is the
simpler of the 2 approaches and may result in fewer dosing errors. The impact
of body weight on the PK of nivolumab is small and the dose-response
relationship is relatively shallow near the 3-mg/kg dose level(the current
licenced dose for nivolumab in melanoma and lung cancer), indicating that
nivolumab can also be administered as a flat dose in combination with
BMS-986016 in this study.
The primary objective of whole study is to look at how safe and how well
managed the investigational drug BMS906016, in combination with nivolumab (BMS
936558), and is for patients with advanced cancers. Part B of the study will be
looking at determining the best dose combination for the two drugs. Once this
has been established, the majority of patients will be entered into part C of
the study, and this will be looking at how effective the drug combination
against the tumour.
Although the data so far indicates that this may be a useful drug in the future
for treating cancers, there is no guarantees at this stage that the drug is
effective against the cancer in human subjects.
The purpose of revised protocol 10 is to
1) add four additional Part B combination dosing cohorts: 480 mg, 960 mg , 1440
mg, and 1600 mg BMS-986016 (relatlimab) + 480 mg nivolumab, every four weeks
(Q4W),
2) change the dose escalation statistical methodology from 3+3+3 to an adaptive
Bayesian Logistic Regression Model (BLRM) Copula design for Part B, which will
more precisely predict the safety profile,
3) change the dose-limiting toxicity period from 8 weeks to 6 weeks
4) add Part E exposure-response evaluation cohorts (melanoma participants who
experienced disease progression on prior anti-PD-1 therapy and melanoma
participants who have not received prior systemic anticancer therapy for
unresectable or metastatic melanoma).
Study objective
This study has been transitioned to CTIS with ID 2023-508067-70-00 check the CTIS register for the current data.
The primary objective is to determine the safety, tolerability, dose-limiting
toxicities (DLTs), and maximum tolerated dose (MTD) of BMS-986016 administered
alone and in combination with nivolumab in subjects with advanced solid tumors.
The co-primary objective in Dose Expansion Part C is to investigate the
preliminary efficacy of BMS-986016 in combination with nivolumab as measured by
overall response rate, disease control rate and duration of response.
The secondary objectives are:
* - To characterize the pharmacokinetics (PK) of BMS-986016 administered alone
and in combination with nivolumab.
* -To investigate the preliminary overall response rate (ORR) and/ or disease
control rate (DCR) of BMS-986016 administered alone and in combination with
nivolumab in subjects with advanced solid tumors in Parts A and B, Dose
Escalation.
Added via revised protocol 12:
Part E:
To evaluate the clinical benefit of the 480 mg BMS-986016 + 480 mg nivolumab
Q4W dosing regimen using Duration Of Response (DOR) in melanoma participants
who have not received prior systemic anticancer therapy for unresectable or
metastatic melanoma and for melanoma participants who experienced disease
progression on prior anti-PD-1 therapy.
-To characterize the immunogenicity of BMS-986016 administered alone and in
combination with nivolumab.
In Parts A, and B, to assess the effect of BMS-986016 administered alone and
in combination with nivolumab on QTc.
Exploratory objectives are:
*- To evaluate safety and tolerability of combination therapy using sequential
infusion therapy.
*- To assess the pharmacodynamic effects of BMS-986016 alone and in combination
with nivolumab based on select biomarkers in the peripheral blood and tumor
biopsy specimens.
* -To characterize T cell function during both BMS-986016 monotherapy and
combination therapy with BMS-986016 and nivolumab.
*- To assess the 2-year landmark overall survival in subjects treated with
BMS-986016 alone and in combination with nivolumab.
*- To explore exposure-response relationships in subjects treated with
BMS-986016 as monotherapy or in combination with nivolumab.
* -To investigate the relationship between clinical efficacy and peripheral and
tumor biomarkers.
The primary objective of Part E is to demonstrate that the 480 mg BMS 986016 +
480 mg nivolumab Q4W dosing regimen provides significantly greater clinical
benefit, manifest as an increased ORR, to participants as compared to the 160
mg BMS 986016 + 480 mg nivolumab Q4W dose; by inter-dose cohort comparison in
melanoma participants who have not received prior systemic anticancer therapy
for unresectable or metastatic melanoma and to historical control for melanoma
participants who experienced disease progression on prior anti-PD-1 therapy.
Study design
This is a Phase 1/2a, open-label study of BMS-986016 administered as a single
agent and in combination with
nivolumab to subjects with advanced solid tumors.
Part A and Part B consist of a 3 + 3 + 3 dose escalation design with BMS-986016
administered as a single agent
(Part A) or in combination with nivolumab (Part B) as sequential infusions in
subjects with advanced solid tumors.
Treatment in Part B will be initiated upon the decision to escalate to the
third dose cohort in Part A (in accordance
with dose escalation rules); subsequently, escalation in the 2 parts will
proceed in parallel. At no point will the dose
of BMS-986016 administered in combination with nivolumab (Part B) exceed doses
of BMS-986016 that have been
demonstrated previously to be safe on the monotherapy dose escalation arm (Part
A).
Part A1 consists of cohort expansion with BMS-986016 monotherapy in 2
disease-restricted cohorts of
approximately 6-12 subjects each. Treatment in Part A1 will be initiated at the
maximum administered dose (MAD)
determined in Part A (i.e., 800mg). The dose selected for Part A1 will not
exceed the MAD in Part A, but dose
selection may change according to assessment of other data including toxicities
and PK and pharmacodynamic data
from Parts A and A1. Subjects in Part A1 may crossover to combination therapy
with nivolumab and BMS-986016
in sequential infusion if they meet pre-defined criteria.
Part C consists of cohort expansion in disease-restricted cohorts using a
multi-stage approach, treated with
sequential infusion of nivolumab and BMS-986016. Cohorts deemed futile (see
sample size section for further
details) at Stage 1 will be discontinued, while those deemed promising may be
expanded further up to 90 to 120
subjects in total after careful evaluation of all available data including the
totality of efficacy, safety profile, and
PK/PD. Otherwise, additional subjects may be treated to collect more data
during Stage 2 in order to make decision
for further expansion. The doses selected for Part C will not exceed the Part B
MTD or MAD, and specific doses
selected may incorporate assessment of other data including toxicities, PK and
pharmacodynamic data from Parts A
and B. Subjects in Part C cannot crossover to Part A1 either.
Subjects in the Netherlands will be asked to take part into Part C (Expansion
Phase) of this study.
The study will consist of 3 periods: Screening (up to 28 days),Treatment (for
up to 96 weeks), and Follow-up (135 days). BMS-986016 (anti-LAG-3) in
combination with nivolumab (BMS-936558) or alone once every 2 weeks on Day 1,
15, 29, and 43 of each treatment cycle. Each IV infusion will take
approximately 1 hour. Response assessment by CT or MRI will occur every 2
months.
Blood tests for haematology, serum chemistry and liver function will be
performed. In addition exploratory blood samples will include, pharmacokinetics
(PK, to measure level of drug in the blood), immunogenicity (to see if the
body's immune system produces proteins that recognise the study treatments),
and biomarker studies (to test for substances in the blood, such as proteins)
will be collected at certain visits throughout the study. These blood tests
serve to check that the patient is fit to receive drug and also monitor for any
potential side effects. Where possible, and in order to minimise the discomfort
to the patient, only one venepuncture will be performed at each visit for the
blood samples to be collected.
A biopsy sample of the tumour will be taken during the screening period if an
archived sample is not available.
Patients will have a CT (or MRI if a CT is not suitable for the patient) scan
at baseline. CT or MRI scans will be done at baseline (both CT of the chest
abdomen and pelvis, and brain and spinal cord). A bone scan may also be
performed at baseline if clinically indicated. During treatment CT scans of the
chest, abdomen and pelvis every two months, until their disease is confirmed to
have progressed. CT of the brain and spinal cord, and bone scans, do not need
to be repeated unless clinically indicated. Bone scans will not be considered a
modality for assessment for measurable
disease. CT scans and bone scans expose patients to radiation. MRI scans are
not thought to be associated with any adverse effects on
health.
Part E consists of advanced melanoma participants. Two cohorts of melanoma
participants will be enrolled in Part E: melanoma participants who experienced
disease progression on prior anti-PD-1 therapy and melanoma participants who
have not received prior systemic anticancer therapy for unresectable or
metastatic melanoma.
In Part E, melanoma participants will be administered either 160 mg BMS-986016
with 480 mg of nivolumab Q4W or 480 mg BMS- 986016 with 480 mg of nivolumab
Q4W; the specific dosing regimen will be dependent on 1) whether the subject
received IO and had progressive disease in an earlier anti-PD-1 therapy and 2)
randomization.
Protocol 11: The treatment duration limit of 8 cycles was removed and the study
duration was updated to up to 5 years.
Intervention
The medicinal interventions include Nivolumab/Anti-Lag-3 combination therapy.
BMS will supply everything to the site taking part.
The Treatment Period consists of up to twelve 8-week treatment cycles. Each
treatment cycle comprises 4 doses of either BMS-986016 alone (Parts A and A1)
or in combination with nivolumab (Part B), administered on Days 1, 15, 29, and
43 of each treatment cycle.
In Parts B and C when both study drugs are given as sequential infusion,
nivolumab will be given first followed by BMS-986016 within 30 minutes of
completing the infusion of nivolumab. Tumor response will be evaluated using
Response Evaluation Criteria for Solid Tumors version 1.1 (RECIST v1.1).
Subjects will be allowed to continue study therapy until the first occurrence
of either: (1) confirmed complete
response (CR), (2) completion of the maximum number of twelve 8-week cycles,
(3) progressive disease (PD), (4) clinical deterioration, and/or (5) meeting
other criteria for discontinuation (Section 3.5). Treatment beyond progression
may be allowed in select subjects with initial RECIST v1.1-defined PD who are
receiving clinical benefit as assessed by the Investigator, tolerating
treatment, and meeting other criteria specified in Section 4.3.4 of the study
protocol version 6.
Subjects who discontinue treatment will enter a 135-day Clinical Follow-up
period.
Melanoma participants who experienced disease progression on prior anti-PD-1
therapy will all receive 480 mg BMS 986016 + 480 mg nivolumab Q4W dose regimen.
Melanoma participants who have not received prior systemic anticancer therapy
for unresectable or metastatic melanoma will be randomized to one of the two
following treatment arms:
* 160 mg BMS-986016 + 480 mg nivolumab Q4W
* 480 mg BMS 986016 + 480 mg nivolumab Q4W
Study burden and risks
Treatments for cancer often have side effects, including some that are
life-threatening. There is the possibility of death occurring as a result of
this treatment and its side effects. There may be risks or side effects which
are unknown at this time.
If subjects experience severe side effects associated with the study drugs, the
study doctor may prescribe medications to treat the side effect(s), future
study drugs may be delayed, or study drugs may be stopped permanently.
What are the risks related to BMS-986016 (anti-LAG-3)?
As of 24 September 2020, approximately 1578 patients have been treated with
relatlimab. 66 Subjects were treated with relatlimab alone and 1512 subjects
received relatlimab in combination with nivolumab. This group of 1578 subjects
consisted of a group of 1406 subjects with solid tumours and 106 subjects with
a tumour affecting the blood or lymphatic system.
The following side effects have been associated with Relatlimab alone.
Relatlimab may cause one or more of the side-effects listed below when given as
a single agent therapy or in combination with nivolumab.
You may experience side effects that are not yet known, which may occur during
or after participating in this study.
These side effects of relatlimab are very common (affect 1 in 10 subjects or
more):
• Fatigue
• Skin rash
These relatlimab side effects are uncommon to common (affecting 1 in 100
subjects to 1 in 10 subjects)
• Amylase increased: lab result associated with pancreas inflammation
• Decreased appetite
• Headache
• Infusion related reaction
• Lipase increased: lab test result associated with pancreas inflammation
• Musculoskeletal pain
• Nausea
What are the risks related to Nivolumab (BMS-936558)?
Nivolumab (BMS-936558) may cause one or more of the side effects listed below.
This information is based on data from cancer subjects in other clinical trials
with nivolumab (BMS-936558). In addition, there may be side effects that are
not yet known that may occur.
Very common side effects of nivolumab (affect more than 1 in 10 patients):
• Diarrhoea
• Feeling tired or lack of energy
• Skin Itching
• Skin Rash
Common side effects (affect between 1 in 10 and 1 in 100 patients) of nivolumab
include:
• Abdominal pain
• Alkaline phosphatase increased: lab test result associated with liver or bone
abnormalities
• Allergic reaction/hypersensitivity
• ALT increased: lab test result associated with abnormal liver function
• Amylase increased: lab test result associated with pancreas inflammation
• AST increased: lab test result associated with abnormal liver function
• Bilirubin (liver function blood test) increased
• Chills
• Constipation
• Cough
• Creatinine increased: lab test result associated with decreased kidney
function
• Decreased appetite
• Dizziness or vertigo (feeling off balance which can lead to dizziness)
• Dry mouth
• Dry skin
• Fever
• Headache
• Increased blood sugar
• Inflammation of the colon
• Inflammation of the mouth
• Lipase increased: lab test result associated with pancreas inflammation
• Loss of colour (pigment) from areas of skin
• Low levels of sodium in the blood
• Low platelet counts (thrombocytopenia): this may increase your risk for skin
bruising, nose bleeds, and bleeding from the gums
• Low red blood cell counts (anemia): this may make you feel weak and tired
• Lung inflammation (pneumonitis): it is possible that nivolumab may cause
inflammation of the tissues of the lung. This adverse effect has been reported
in patients treated with nivolumab. While many patients with X-ray or CT
abnormalities have not developed any symptoms, some patients have developed
mild to severe symptoms and in rare cases, death has occurred as a result of
their lung inflammation. Signs and symptoms of lung inflammation may include
difficulty breathing, pain or discomfort while breathing, chest pain, cough,
shortness of breath, increased rate of breathing, fever, low blood oxygen
levels, or fatigue
• Nausea
• Pain in the muscles, bones, ligaments, tendons and nerves
• Reaction related to infusion of the medicine. The symptoms may include but
not limited to fever, rash, pain, swelling
• Redness of skin
• Shortness of breath
• Swelling, including face, arms, and legs (oedema)
• Thyroid gland function decreased or may be increased; increased thyroid
stimulating hormone - a lab test result associated with abnormal thyroid
function
• Tingling, burning, numbness or weakness, possibly in arms, legs, hands and
feet
• Vomiting
Uncommon side effects (affects between 1 in 100 and 1 in 1000 patients) of
nivolumab include:
• Bronchitis : inflammation of the lining of bronchial tubes, which carry air
to and from the lungs
• Low white blood cell counts (neutropenia): these put you at higher risk for
infection
• Decreased secretion of hormones produced by adrenal glands
• Decreased thyroid stimulating hormone - a lab test result associated with
abnormal thyroid function
• Dehydration
• Diabetes (a disease that results in too much sugar in the blood)
• Dry eye
• Erythema multiforme): a skin disorder that's considered to be an allergic
reaction to medicine or an infection. Symptoms may include symmetrical, red,
raised skin areas that can appear all over the body, more noticeable on the
fingers and toes. These patches often look like "targets" (dark circles with
purple-grey centers)
• Difficulty Falling and/or staying asleep (Insomnia)
• Hair loss
• Heart rate increased
• Heart rhythm abnormal
• High Blood Pressure
• Hives
• Inflammation of the eye
• Inflammation of the kidney
• Inflammation of the pancreas
• Inflammation of the pituitary gland
• Inflammation of the stomach
• Inflammation of the thyroid gland
• Joint pain or stiffness
• Kidney function failure, kidney disease
• Liver inflammation
• Low blood pressure
• Underactive function of the pituitary gland situated at the base of the brain
• Skin disease with thickened patches of red skin, often silvery scales
(Psoriasis)
• Respiratory failure: a condition in which not enough oxygen passes from your
lungs into your blood, or when your lungs cannot properly remove carbon dioxide
• Malfunctioning pituitary gland situated at the base of the brain
• Upper respiratory tract infection - a common viral/ bacterial infection that
affects the nose, throat, and airways
• Vision blurred
• Pemphigoid: blistering of the skin or mouth caused by the immune system
attacking healthy tissue
Rare side effects (affects between 1 in 1000 and 1 in 10,000 patients) of
nivolumab include:
• Autoimmune hemolytic anemia: a malfunction of the immune system that produces
autoantibodies, which attack red blood cells as if they were foreign
substances to the body
• Cranial Nerve disorder
• Damage to the protective covering of the nerves in the brain and spinal cord
• Diabetes complications resulting in excess blood acids
• Disease caused by the body*s immune system attacking healthy organs
• Drug induced liver injury
• Double vision
• Guillain-Barre syndrome, an autoimmune disorder associated with progressive
muscle weakness or paralysis
• Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of
the lymph nodes which causes the lymph nodes to become enlarged, inflamed and
painful, commonly affecting lymph nodes of the neck and possibly as
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Age
Inclusion criteria
-For Dose escalation: subjects with cervical, ovarian, bladder and CRC, head
and neck, gastric and hepatocellular cancer naive to immuno-oncology agents;
1st line melanoma and NSCLC; NSCLC progressing while on or after therapy with
anti-PD1/anti-PDL-1 and melanoma subjects progressed while-on or after
treatment with anti-PD1 or anti-PDL1 with/out anti-CTLA-4.
-For Dose Expansion: all of the above in escalation except for cervical,
ovarian bladder and CRC
-Progressed, or been intolerant to, at least one standard treatment regimen
-Received any number of prior treatment regimens
-ECOG performance status of 0 or 1
-At least 1 lesion with measurable disease at baseline
-Availability of an existing tumor biopsy sample (or consent to allow
pre-treatment tumor biopsy if sample not available
Exclusion criteria
- Primary CNS tumors or solid tumors with CNS metastases as the only site of
active disease, - Autoimmune disease, - Encephalitis, meningitis, or
uncontrolled seizures in the year prior to informed consent, - Uncontrolled CNS
metastases
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 | CTIS2023-508067-70-00 |
| EudraCT | EUCTR2014-002605-38-NL |
| ClinicalTrials.gov | NCT01968109 |
| CCMO | NL57142.031.16 |