This study has been transitioned to CTIS with ID 2023-507475-21-00 check the CTIS register for the current data. Primary objective:To evaluate the efficacy of cobolimab + dostarlimab + docetaxel relative to docetaxel alone in participants with…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall Survival (OS) defined as survival from the date of randomization to
the date of death by any cause
Secondary outcome
Secondary:
OS defined as survival from the date of randomization to the date of death by
any cause
Confirmed ORR defined as the proportion of participants who have achieved
confirmed CR or confirmed PR, evaluated using RECIST v1.1 based on Investigator
assessment
• PFS defined as the length of time until disease progression, from the time of
randomization to the earliest date of assessment of disease progression based
on RECIST v1.1 by Investigator assessment or death by any cause
• DOR defined as the time from first documented response (CR/PR) until the time
of first documentation of disease progression based on RECIST v 1.1 by
Investigator assessment
or death, whichever occurs first
• TTD in lung cancer defined as time from randomization to meaningful
deterioration on a composite endpoint of dyspnea, chest pain, and cough, from
the EORTC-QLQ-LC13
• Change from baseline as assessed by the EORTC-QLQ-C30 and the EORTC-QLQ-LC13
domains
The incidence of TEAEs, SAEs, irAEs, TEAEs leading to death, and AEs leading to
discontinuation occurring while participants are on treatment or up to 90 days
after the last dose of study treatment. Clinical laboratory parameters
(hematology, chemistry, thyroid function, and urinalysis), vital signs, ECOG
performance status, ECG parameters, physical examinations, and usage of
concomitant medications will be collected.
Confirmed ORR defined as the proportion of participants who have achieved
confirmed CR or confirmed PR, evaluated using iRECIST based on Investigator
assessment
• PFS defined as the length of time until confirmed disease progression from
the time of randomization to the earliest date of iRECIST iCPD by Investigator
assessment or death by any cause. Additional PK parameters of cobolimab and
dostarlimab will be determined, if appropriate.
Cobolimab and dostarlimab ADAs (including NAbs to dostarlimab/cobolimab), with
associated drug concentrations. Number and percentage of participants who
develop detectable ADAs and NAbs.
Exploratory:
Blood-based biomarkers may include, but are not limited to, serum cytokines,
circulating immune cells, and ctDNA.
Tumor-based biomarkers will assess baseline expression of TIM-3 and PD-L1 and
correlate with ORR and changes in immune cells, such as CD8 T cells, following
treatment, in paired biopsies. Tumor-based biomarkers, where tissue is
available, may also include gene expression profiling for
immune-related and tumor-related proteins and assessment of tumor genome for
mutations and/or genomic alterations.
Change from baseline in the NSCLC-SAQ
• Frequency and severity of patient-reported AEs based on the PRO-CTCAE and the
FACT-GP5
• Change from baseline in overall symptom severity on the PGIS/PGIC
• Change from baseline as assessed by the EQ-5D-3L
Number and duration of non protocol healthcare encounters such as provider
visits, emergency room visits, hospitalizations, medications, tests, and
procedures
Background summary
In this study, cobolimab in combination with dostarlimab and docetaxel (taxane
chemotherapy) is being investigated to treat advanced NSCLC, as this patient
population represents a high unmet medical need. This study and select cohorts
of the ongoing Phase 1 Study 4020-01-001 (AMBER; GSK Study 213348) and the
ongoing Phase 1 Study 204691 (INDUCE-1) represent the only ongoing studies of
cobolimab in NSCLC by the Sponsor at this time. In the AMBER expansion cohorts
B2 (dostarlimab 500 mg + cobolimab 100 mg), B3 (dostarlimab 500 mg + cobolimab
300 mg) and B4 (dostarlimab 500 mg + cobolimab 900 mg), eligibility
requirements include histologically proven advanced or metastatic NSCLC that
progressed following treatment with an anti-PD-(L)1 antibody and no limit on
prior lines of anticancer therapy for advanced or metastatic disease.
Eighty-four participants were enrolled in Cohorts B2, B3, and B4 as of 01
December 2019.
There was a total of 10 participants with a partial response (PR) across all 3
cohorts, 6 of which
were confirmed by RECIST v1.1. Signs of combination activity were greater in
Cohort B3
(300 mg cobolimab) compared to Cohort B2 (100 mg cobolimab) or Cohort B4 (900 mg
cobolimab); there were 4 confirmed partial responses (cPRs) by RECIST v1.1 in
Cohort B3
compared to 1 cPR each in Cohorts B2 and B4. Across all cohorts, durable
responses and stable
disease (SD) were observed following treatment with cobolimab + dostarlimab,
with
5 participants beyond a year of treatment. As of the data cut, 3 participants
remained on
treatment.
Lung cancer is the most common cause of cancer mortality globally and the
second most
common cancer in both men and women. Most recent lung and bronchus cancer
incidence rates in the US from the Surveillance, Epidemiology, and End Results
program estimate an incidence rate of 54.9 per 100,000 from 2016 data. The 2
major forms of lung cancer are NSCLC and small cell lung cancer. NSCLC is a
heterogeneous disease that consists of adenocarcinoma, large cell carcinoma,
and squamous cell carcinoma, and comprises approximately 84% of all lung
cancers. The average age of diagnosis is approximately 70 years old. Despite
advances in early detection and standard treatment, NSCLC is often diagnosed at
an advanced stage, has poor prognosis, and is the leading cause of cancer
deaths worldwide. In the US, the 5 year OS rate of all stages of NSCLC is
approximately 19%, with advanced patients (Stage IIIB/IV) having a 5 year OS
rate of <5%.
PD-(L)1 represents an immune inhibitory mechanism employed by tumors to subvert
the
immune response and disruption of this axis enhanced the lysis of tumor cells
by T cells.
Multiple clinical studies in tumors such as melanoma, renal cell carcinoma, and
NSCLC have
yielded positive data using anti-PD-(L)1-targeted therapies.
The introduction of anti-PD-(L)1 therapy in the first-line setting has improved
outcomes for
patients with NSCLC without an aberration in a driver oncogene. However, many
patients with NSCLC do not respond to first-line anti-PD-(L)1 therapy (45% ORR
in pembrolizumab monotherapy patients with tumor proportion score [TPS] >=50%;
48% ORR in pembrolizumab + chemotherapy patients with nonsquamous NSCLC), and
most of those who do respond will typically progress within a year. For
patients who progress on an anti-PD-(L)1 antibody and platinum-based
chemotherapy, there are no drugs approved, nor is there an established standard
of care in this setting. Drugs approved for second-line treatment of NSCLC
following a platinum-based regimen (docetaxel, ramucirumab in combination with
docetaxel, or pemetrexed [nonsquamous NSCLC only]) provide limited benefits
with response rates ranging from 5.5% to 23%, progression-free survival (PFS)
of 3 to 4.5 months
Study objective
This study has been transitioned to CTIS with ID 2023-507475-21-00 check the CTIS register for the current data.
Primary objective:
To evaluate the efficacy of cobolimab + dostarlimab + docetaxel relative to
docetaxel alone in participants with advanced NSCLC who have progressed on
prior anti-PD-(L)1 therapy and
Chemotherapy.
To evaluate the efficacy of dostarlimab + docetaxel relative to docetaxel alone
in participants with advanced NSCLC who have progressed on prior anti-PD-(L)1
therapy and chemotherapy
Secondary Objectives:
To evaluate the efficacy of cobolimab + dostarlimab + docetaxel relative to
dostarlimab + docetaxel
To evaluate additional measures of clinical benefit for cobolimab + dostarlimab
+docetaxel relative to docetaxel alone
To evaluate additional measures of clinical benefit for dostarlimab + docetaxel
relative to docetaxel alone
To evaluate additional measures of clinical benefit for cobolimab + dostarlimab
+ docetaxel relative to dostarlimab + docetaxel
To evaluate the safety and tolerability of cobolimab + dostarlimab + docetaxel
and dostarlimab + docetaxel vs docetaxel alone
Exploratory:
To evaluate confirmed ORR and PFS by iRECIST
To characterize the PK of cobolimab, dostarlimab, and docetaxel
To assess the immunogenicity of cobolimab and dostarlimab at defined time points
To assess biomarkers related to studytreatment in all treatment arms
To assess PROs for treatment efficacy and tolerability in all treatment arms
using
targeted PRO instruments
To evaluate the healthcare resource utilization in all treatment arms
Study design
A multicenter, parallel-group treatment, Phase 2/3 open-label, 3-arm study
comparing
cobolimab + dostarlimab + docetaxel to dostarlimab + docetaxel to docetaxel
alone for efficacy in male and female participants aged 18 years and older with
advanced NSCLC who have progressed on prior anti-PD-(L)1 therapy and
chemotherapy. Crossover between treatment arms will not be allowed in this
study.
The 3 treatment arms will be as follows:
1. Arm A: Cobolimab + dostarlimab + docetaxel
2. Arm B: Dostarlimab + docetaxel
3. Arm C: Docetaxel
Intervention
Participants will be randomized 2:2:1 into the 3 study treatment arms (groups)
and dosed with
the previously listed treatments as follows, following any visit-mandated
assessments:
•Arm A: Cobolimab + dostarlimab + docetaxel
* 300 mg cobolimab via a 30 (-5 and +15)-minute IV infusion Q3W (administered
first)
* 500 mg dostarlimab via a 30 (-5 and +15)-minute IV infusion Q3W (administered
second)
* 75 mg/m2 docetaxel via a 60-minute IV infusion Q3W for a minimum of 4 cycles
(administered third/last)
Arm B: Dostarlimab + docetaxel
* 500 mg dostarlimab via a 30 (-5 and +15)-minute IV infusion Q3W (administered
first)
* 75 mg/m2 docetaxel via a 60-minute IV infusion Q3W for a minimum of 4 cycles
(administered second/last)
Arm C: Docetaxel
* 75 mg/m2 docetaxel via a 60-minute IV infusion Q3W for a minimum of 4 cycles
Study burden and risks
Cobolimab:
Very common side effects:
• Skin problems may include rash and itching (Immune-mediated Skin Reactions)
• Lung problems may include symptoms like shortness of breath, chest pain, new
or worse cough (Immune-mediated Pneumonitis)
• Hormone gland problems especially the thyroid, pituitary and adrenal glands
(Immune-mediated Endocrinopathy)
There are rare but serious immune-related adverse events which have been seen
when cobolimab was used in combination with other medicines:
• Tingling, numbness, loss of sensation, or a burning sensation in the
extremities (peripheral motor neuropathy)
Dostarlimab:
These side effects are considered (very) common in patients who took
dostarlimab:
• Anaemia
• Hypothyroidism
• Nausea
• Vomiting
• Diarrhoea
• Pruritus
• Rash
• Pyrexia
• Increased levels of substances in the blood produced by the liver which may
be a sign of liver injury (AST increased; ALT increased)
• Adrenal insufficiency
• Hyperthyroidism
• Pneumonitis
• Pancreatitis
• Colitis
• Myalgia
• Chills
• Inflammation of the liver (hepatitis)
These side effects are considered uncommon in patients who took dostarlimab:
Autoimmune haemolytic anaemia
• Thyroiditis
• Hypophysitis
• Diabetic Ketoacidosis
• Type 1 Diabetes Mellitus
• encephalitis
• Uveitis
• myocarditis
• Polymyalgia rheumatica
• Nephritis
• Myasthenia gravis
. Immune Mediated Arthritis (joint pain).
• Gastritis
• Esophagitis
• Enteritis
• Vasculitis gastrointestinal
• Myositis
• Systemic Inflammatory Response Syndrome
These are rare but serious immune-related adverse events which have been seen
when dostarlimab was used alone or in combination with other medicines:
• Hemophagocytic Lymphohistiocytosis
• Guillain-Barré syndroom
• peripheral motor neuropathy
• eosinophilic fasciitis
Other risks called class effects that have been seen in patients receiving
other drugs that work like dostarlimab. These effects could also occur with
dostarlimab or cobolimab. The most significant class related side effects are
*immune-related*, side effects caused by increased activity of the immune
system, which can affect multiple organs of the body including gastrointestinal
tract, endocrine system, cardiovascular system, lungs, liver, skin,
musculoskeletal system and nervous system. These other immune related side
effects may be life threatening or fatal.
Infusion-related reactions which can occur within 24 hours after receiving an
intravenous infusion, or which can be delayed for up to about 2 weeks.
Infusion-related reactions may include dizziness or fainting, flushing, rash,
fever, chills, shortness of breath, increased or decreased blood pressure,
increased heart rate, swelling of the lips, tongue or face, feeling sick to
your stomach, back pain or pain at the site of infusion. Although
infusion-related reactions are usually reversible, they can be severe or life
threatening (Infusion related reactions).
Risks associated with study procedures/tests are listed below:
• Blood draws: When giving blood, the patient may feel faint or experience mild
pain, bruising, irritation or redness from the needle.
• CT scans: The cumulative radiation exposure from these tests is considered
small and is not likely to adverse ly affect the patient or the patient*s
disease. However, the effects of radiation add up over a lifetime. It is
possible that having several of these tests may add to the patients risk of
injury or disease.
• MRI: Some people cannot have an MRI because they have some type of metal in
their body. Some patients are scared or anxious in small places
(claustrophobic). The MRI scanner makes loud banging noises while scanning, ear
plugs or specially designed headphones will be used to reduce the noise.
Considering the measures taken to minimize risk to study participants, the
potential risks identified in association with cobolimab in combination with
dostarlimab and docetaxel are justified by the anticipated benefits that may be
afforded to participants with NSCLC who progressed post-treatment with an
anti-PD-(L)1 antibody and platinum-based chemotherapy.
The lack of benefit of current treatment options to patients with NSCLC may be
due to additional immunosuppressive mechanisms, such as those mediated by
TIM-3. Early combination treatment enables the assessment of TIM-3 and PD-1
blockade to address de novo resistance to anti-PD-1 blockade while preventing
one of the mechanisms that may result in resistance to anti-PD-1 monotherapy.
To summarize, the possibility of improving the clinical benefit of
immunotherapies for patients with advanced/metastatic NSCLC who have limited
treatment options presents an opportunity to improve clinical outcomes. Given
the clinical activity of antibodies targeting the PD-1 axis in a broad range of
solid tumors, patients with NSCLC are expected to derive clinical benefit with
the addition of TIM-3 blockade and taxane chemotherapy.
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Listed location countries
Age
Inclusion criteria
1. Participant is >=18 years old
2. Participant has histologically or cytologically proven advanced or
metastatic NSCLC,
and only squamous or nonsquamous cell carcinoma.
3. Participant has received no more than 2 prior lines of therapy for advanced
or metastatic disease, which must only include a platinum-based doublet
chemotherapy regimen and an anti-PD-(L)1 antibody. Participants previously
treated with targeted therapies, including angiogenesis inhibitors are not
eligible.
a. Two components of treatment must have been received in the same line or as
separate
lines of therapy as follows:
• A maximum of 1 line of therapy containing a platinum-based chemotherapy in the
metastatic setting
and
• A maximum of 1 line of therapy containing an anti-PD-(L)1 antibody
4. Participant has measurable disease, that is, presenting with at least 1
measurable lesion
per RECIST v1.1
5. Participant has documented radiological disease progression on prior
platinum-based
chemotherapy and on prior anti-PD-(L)1 therapy according to RECIST v1.1.
6. Participant agrees to submit an archival FFPE tumor tissue specimen that was
collected
on or after diagnosis of metastatic disease from location(s) not irradiated
prior to biopsy.
7. Participant has documented PD-L1 status by the 22C3 pharmDx assay
(Agilent/Dako), the SP263 assay (Roche) or a LDT with published evidence of
concordance with the 22C3 pharmDx assay. If a prior PD-L1 result by this
testing methods is not available at the time of Screening, the participant must
submit archival or fresh tumor tissue to be tested locally using 1 of these
testing methods, or, if not available, centrally, using the 22C3 pharmDx assay.
8. Participant has an ECOG performance status score of 0 or 1.
9. Participant has a life expectancy of at least 3 months and is anticipated to
be able to complete 4 cycles of docetaxel treatment.
10. Participant has adequate organ function as defined in the protocol.
11. Participant has recovered to Grade <=1 from any prior treatment-related
toxicities at the time of randomization. A participant with Grade 2 alopecia is
an exception to this criterion and may qualify for this study.
12. Contraceptive use by male and female participants should be consistent with
local regulations regarding the methods of contraception for those
participating in clinical
studies.
Exclusion criteria
1. Participant has been previously treated with an anti-PD-(L)1 or anti-PD-L2
agent that resulted in permanent discontinuation due to an AE.
2. Participant has been previously treated with an anti-TIM-3 or anti-CTLA-4
agent or docetaxel.
3. Participant has a documented sensitizing EGFR, ALK, or ROS-1 mutation.
Participants
whose tumors have not been tested for these driver mutations and therefore who
have unknown driver mutation status are not eligible. Participants with
squamous histology do not need to be tested for these driver mutations.
4. Participant had radiological or clinical disease progression <=8 weeks after
initiation of prior
anti-PD-1 or anti-PD-L1 antibody. The clinical disease progression should have
been confirmed by a subsequent radiological scan.
5. Participant has received radiation to the lung that is >30 Gy within 6
months prior to the
first dose of study treatment.
6. Participant has completed palliative radiotherapy within 7 days prior to the
first dose of
study treatment.
7. Participant is ineligible if any of the following hepatic characteristics
are present:
a. Alanine aminotransferase (ALT >2.5×ULN
b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
>1.5×upper limit of normal (ULN) concomitant with alkaline phosphatase (ALP)
>2.5×ULN
c. Bilirubin >1×ULN
d. Current active liver or biliary disease
8. Participant has a corrected QT interval (QTc) >450 msec
9. Participant has had major surgery within 3 weeks prior to the first dose of
study treatment or has not adequately recovered from any AEs (Grade <=1) and/or
complications from any major surgery.
10. Participant has an additional malignancy or a history of prior malignancy,
with the exception of adequately treated basal or squamous skin cancer,
cervical carcinoma in situ, or bladder carcinoma in situ without evidence of
disease, or had a malignancy treated with curative intent and with no evidence
of disease recurrence for 5 years since the initiation of that therapy.
11. Participant has known new or progressive brain metastases and/or
leptomeningeal
metastases.
12. Participant has tested positive for the following at screening or within 3
months before the first dose of the study treatment:
a. presence of hepatitis B surface antigen
b. presence hepatitis C antibody in the absence of an RNA test voor hepatitis C
virus.
13. Participant has an active infection requiring systemic therapy within 1
week prior to the anticipated first dose of study treatment.
14. Participant has known HIV (positive for HIV-1 or HIV-2 antibodies).
15. Participant has active autoimmune disease that required systemic treatment
in the past 2 years, is immunocompromised in the opinion of the Investigator,
or is receiving systemic immunosuppressive treatment.
17. Participant has symptomatic ascites or pleural effusion.
18. Participant has current interstitial lung disease, current pneumonitis, or
a history of pneumonitis that required the use of oral or IV glucocorticoids to
assist with management.
19. Participant has a history or current evidence of any medical condition,
therapy, or laboratory abnormality that might confound the study results,
interfere with participation for the full duration of the study treatment, or
indicate it is not in the best interest of the participant to participate.
20. Participant has clinically active diverticulitis, intra-abdominal abscess,
gastrointestinal
obstruction, or peritoneal carcinomatosis.
21. Participant has pre-existing peripheral neuropathy that is Grade >=2
(NCI-CTCAE) v5.0 criteria.
22. Participant has received a live vaccine within 30 days of the first dose of
study treatment.
23. Participant has a sensitivity to any of the study treatments, or components
thereof, or a
history of drug or other allergy.
24. Participant is unable to interrupt aspirin or other nonsteroidal
anti-inflammatory drugs
(NSAIDs).
25. Participant has received prior anticancer therapy within 21 days, or less
than 5 times the half-life of the most recent therapy prior to study Day 1,
whichever is shorter.
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 |
|---|---|
| Other | 213410/COSTAR |
| EU-CTR | CTIS2023-507475-21-00 |
| EudraCT | EUCTR2020-003433-37-NL |
| CCMO | NL78624.056.21 |