Primary: • Part 1:To evaluate the efficacy of NIR178 and PDR001 combination in patients with selected advanced solid tumors and diffuse large B cell lymphoma (DLBCL). • Part 2: To assess the efficacy of several intermittent dosing schedules of…
ID
Source
Brief title
Condition
- Other condition
- Lymphomas non-Hodgkin's B-cell
- Respiratory tract neoplasms
Synonym
Health condition
Neoplasmata, maligne, solide tumoren
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Part 1: Overall Response Rate (ORR)
• Part 2: ORR
• Part 3: ORR.
Secondary outcome
Disease control rate, Duration of response, Progression free survival, 2y
Overall survival rate. Adverse events. Change from baseline in tumor
infiltrating lymphocytes. PK parameters, Antidrug-antibodies.
Background summary
Combination therapies using multiple inhibitors of immune function can
significantly improve response rates. For example, a nivolumab/ipilimumab
combination providing blockade of the PD-1 and CTLA-4 immune checkpoints
significantly improved responses for patients with advanced melanoma. Expanding
the depth, breadth and durability of responses to treatment is now an important
focus of clinical oncology research.
NIR178 activates the immune system by blocking the adenosine A2a receptor
(A2aR). Two healthy volunteer studies were conducted with NIR178 and there is
one ongoing Phase I/Ib trial of NIR178 as single agent and in combination with
PDR001 in patients with advanced non-small cell lung cancer. See protocol page
27-28 for details.
PDR001 is an anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to
PD-1. In the mean time 11 early phase studies with PDR001 as a monotherapy or
in combination are ongoing. As observed with other PD-1 inhibitors,
immune-mediated toxicities observed with PDR001 are reversible in many cases.
In some cases, they may require treatment with corticosteroids. Certain
toxicities are expected to be lifelong and may require replacement therapy with
hormones. Based on the preliminary data, PDR001 was well tolerated with a
safety profile similar to those of other marketed anti-PD-1 antibodies.
The purpose of this phase 2 study is to evaluate the efficacy and safety of
NIR178 in combination with PDR001 in multiple solid tumors and diffuse large
B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to
optimize immune activation through inhibition of A2aR.
The study has three parts:
• Part 1: Multi-arm Bayesian adaptive signal finding design in 7 types of solid
tumors and non-Hodgkin lymphoma.
• Part 2: NIR178 schedule exploration in NSCLC.
• Part 3: Further evaluation of intermittent dosing schedules of NIR178 in
combination with PDR001 in TNBC and one additional tumor types, if part 2
identifies an intermittent dosing schedule of NIR178 as warranting further
exploration.
Study objective
Primary:
• Part 1:To evaluate the efficacy of NIR178 and PDR001 combination in patients
with selected advanced solid tumors and diffuse large B cell lymphoma (DLBCL).
• Part 2: To assess the efficacy of several intermittent dosing schedules of
NIR178 in combination with PDR001 in NSCLC.
• Part 3: To evaluate efficacy of intermittent dosing schedule of NIR178 in
TNBC and another tumor type. This additional tumor type will be selected based
on the emerging data from part 1 and may only begin enrollment following
implementation via formal protocol amendment.
Secondary:
Efficacy of NIR178 plus PDR001 in selected advanced solid tumors and lymphoma,
safety and tolerability of the combination, changes in the immune infiltrate in
tumors, pharmacokinetics (PK), immunogenicity of PDR001.
Study design
Multi-center, open label, phase 2 study to evaluate efficacy of the NIR178 and
PDR001 combination in solid tumors and non-Hodgkin lymphoma.
The study has three parts:
• Part 1: Multi-arm Bayesian adaptive signal finding design in 7 types of solid
tumors and non-Hodgkin lymphoma.
• Part 2: NIR178 schedule exploration in NSCLC.
• Part 3: Further evaluation of intermittent dosing schedules of NIR178 in
combination with PDR001 in TNBC and one additional tumor types, if part 2
identifies an intermittent dosing schedule of NIR178 as warranting further
exploration.
Patients will receive NIR178 160 mg either BID continuously or based on the
assigned intermittent schedule within 60 minutes prior to PDR001 infusion.
PDR001 will be administered via IV infusion over 30 minutes once every 4 weeks.
Treatment cycles of 4 weeks.
Treatment until disease progression or unacceptable toxicity.
Patient numbers: Part 1: n=80-240 (depending on treatment effects in the
various disease groups. Part 2: n=60. Part 3: n=40.
Intervention
Treatment with NIR178 in combination with PDR001.
Study burden and risks
Risk: Adverse effects of the combination of NIR178 plus PDR00 and risks
associates with the assessments.
Burden: Cycles of 4 weeks. 6 visits during cycle 1, 2 during cycles 2-3 and 1
during every cycle thereafter. Visit duration mostly 1-4 hours.
IV infusions of PDR001 on day 1 of every cycle. Infusions of 250 mL. Duration
of PDR001 infusion standard 0,5 hour (up to 2 hours is accepted).
Physical examination: day 1 (and 15 during cycle 1) of every cycle, screening,
end of treatment.
Blood tests (10-30 mL/occasion):
• Safety tests: 2 times during cycle 1-3, once during every cycle thereafter,
screening, once during follow-up.
• PK: 6 visits during cycle 1, 2 visits during cycle 3, once during cycles 4,
5, 6. 2 visits with 9 serial blood draws. Approx. 190 mL in total).
• Biomarkers: 4 times. Approx. 80 mL in total.
ECG: once (twice during cycle 1) during every cycle, screening, end of
treatment.
CT-/MRI scan: every 8-12 weeks.
Bone marrow aspiration/biopsy (lymphoma patients only): once.
3 tumor biopsies (1st might be replaced by recent archival material).
Optional: tumor biopsy at disease progression.
Optional use of the remaining blood and tissue for future research.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
• Males and females >=18 years of age.
• Histologically documented advanced or metastatic solid tumors or lymphoma.
- Part 1: histologically confirmed advanced or metastatic renal cell
carcinoma, pancreatic cancer, urothelial cancer, head and neck cancer,
non-Hodgkin lymphoma, microsatellite stable or mismatch repair colorectal
cancer, triple negative breast cancer or cutaneous melanoma (confirmed BRAF
V660E status) or mCRPC
- Part 2: histologically confirmed advanced or metastatic NSCLC (EGFR and ALK
genotype).
- Part 3: histologically confirmed advanced or metastatic TNBC
• Tumor amenable to biopsy. See protocol page 52 for details.
• Part 1 - 3 only: Patients (other than those with DLBCL) must previously have
received at
least 1 and no more than 3 prior lines of therapy for their disease.
• No prior immunotherapy, except for cutaneous melanoma, I/O pre-treated
head/neck ca, and TNBC patients enrolled in part 3. An additional tumor type
might be added based on data.
• Measurable disease.
• ECOG performance status 0, 1, 2.
Refer to section Protocol section 5.2 for more detailed information regarding
prior therapy per tumor type
Exclusion criteria
• History of another primary malignancy. .
• Active or prior documented autoimmune disease within the past 2 years.
• History of interstitial lung disease or non-infectious pneumonitis.
• Ongoing or prior treatment with A2aR inhibitors. Patients previously treated
with A2aR inhibitors for non-oncologic indications may be considered for
enrollment on a case by case basis.
• More than 2 or 3 prior lines of therapy (depending on the tumor type)
• Clinical laboratory abnormalities (within 21 days before 1st dose): Absolute
neutrophil count <1.0 x 109/L - Platelet count <100 x 109/L (for lymphoma <75 x
109/L , Hemoglobin (Hgb) <9 g/dL (5,59 mmol/l), Creatinine > 1. x upper limit
of normal (ULN) - Total bilirubin >1.5 x ULN - ALT and AST (liver) >3 x ULN
• History or current cardiac disease indicating significant risk of safety such
as uncontrolled cardiac disease (see criterion 29 protocol section 5.3)
• Mean QTcF >470 ms.
• Current or prior use of immunosuppressive medication within 28 days before
the first dose of PDR001.
•Smoking must be discontinued at least 7 days prior to initiating study drug
administration; smoking cessation products may be used.
For more details see protocol section 5.3
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 | EUCTR2017-000241-49-NL |
| ClinicalTrials.gov | NCT03207867 |
| CCMO | NL62490.056.17 |