Primary objectives:* Safety run-in stage: determine the recommended phase two dose for therandomised phase* Randomised stage: to determine efficacy of IMP321 combined with weekly paclitaxel compared to weekly paclitaxel plus placebo in hormone…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression Free survival
Secondary outcome
Secondary Efficacy Endpoints
* To assess overall survival (OS)
* To assess adverse events according to the current National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) and other safety
parameters
* To assess the time to next treatment (TTNT), objective response rate (ORR)
according to RECIST 1.1, time to and duration of response and duration of
stable disease
* To assess the plasma concentration time profile of IMP321 and derived PK
parameters
* To assess the quality of life (QOL)
* To assess development of anti-drug (IMP321) antibodies (ADA)
Background summary
Lymphocyte activation gene 3 protein (LAG-3) is a transmembrane protein found
on activated T and natural killer (NK) cells and a key mediator of immune
responses. IMP321 is a recombinant soluble human LAG-3Ig fusion protein which
is under development as a cancer immunotherapeutic agent. Like endogenous
LAG-3, IMP321 binds to major histocompatibility complex (MHC) class II antigen
presenting cells (APCs) such as dendritic cells (DCs), and triggers a T helper
(Th)1 response and T cell proliferation.
Nine clinical studies with IMP321 have been conducted to date, including three
evaluating IMP321 as a monotherapy or as part of chemo-immunotherapy (one each
in metastatic renal cell carcinoma [MRCC], metastatic breast cancer [MBC], and
pancreatic cancer) and six evaluating IMP321 as a vaccine adjuvant (two in
healthy volunteers, three in melanoma, and one in prostate cancer).
The proposed Phase IIb clinical study aims to investigate the safety and
efficacy of the active immunotherapy IMP321 in combination (adjunctive) with
paclitaxel chemotherapy in patients with hormone receptor-positive metastatic
breast cancer.
Study objective
Primary objectives:
* Safety run-in stage: determine the recommended phase two dose for
therandomised phase
* Randomised stage: to determine efficacy of IMP321 combined with weekly
paclitaxel compared to weekly paclitaxel plus placebo in hormone
receptor-positive metastatic breast cancer patients
Secondary Objectives
* to further characterise the anti-tumour activity of IMP321 in combination
with weekly paclitaxel in terms of clinical responses and clinical outcomes and
compare it to placebo
* to examine the safety and tolerability of IMP321 in combination with weekly
paclitaxel and compare it to placebo
* to characterise the pharmacokinetic (safety run-in only) and immunogenic
properties of IMP321
* to assess the quality of life related to IMP321 compared to placebo
Exploratory Objectives
* To characterise the immune response of patient and identify biomarkers
Study design
Multicentre, placebo-controlled, double-blind, 1:1 randomised Phase IIb study
in female hormone receptor-positive metastatic breast cancer patients.
The study comprises of two stages. In the open-label, safety run-in stage the
Recommended Phase 2 Dose (RPTD) of IMP321 in combination with paclitaxel will
be confirmed. In the placebo-controlled, double-blind randomisation stage,
paclitaxel + IMP321 at the RPTD will be compared to paclitaxel + placebo.
Stage 1 - open label, safety run-in (dose optimization): The study will be
initiated with an open-label, safety run-in stage to assess the comparative
safety, tolerability, pharmacokinetics and induction of immune responses of 6
mg (cohort 1) and 30 mg (cohort 2) of IMP321 as adjunctive to paclitaxel
chemotherapy.
Stage 2 - placebo-controlled, double-blind randomisation: In the second stage
of the study a total number of 226 patients will be randomised 1:1 to receive
either paclitaxel + IMP321 at the RPTD or paclitaxel + placebo in a
double-blinded fashion. Patients will be stratified by ECOG performance status
(0 versus 1).
IIn both study stages, treatment consists of a chemo-immunotherapy phase
followed by a maintenance phase. The chemo-immunotherapy phase consists of 6
cycles of 4 weeks. During each cycle the patient will receive weekly paclitaxel
(80 mg/m²) at Days 1, 8 and 15 with adjunctive treatment of study agent, either
IMP321 or placebo, on Days 2 and 16 of each 4-week cycle. After completion of
the 6-cycle chemo-immunotherapy phase, responding or stable patients will
receive study agent (IMP321 or placebo) every 4 weeks during the maintenance
phase for additional 12 injections.
A patient will stay on treatment until disease progression, unacceptable
toxicity, completion of the maintenance phase or discontinuation for any other
reason.
Screening should occur during the 3 weeks prior to start of paclitaxel
treatment (Cycle 1/ Day 1). Upon start of study treatment, patients will be
followed for PFS and OS. PFS will be radiologically assessed at the study sites
until progressive disease (PD), death, withdrawal of consent, loss to
follow-up, or until the end of the study, whichever occurs first. Radiological
assessment will be performed at interval of 8 weeks while patients are on study
treatment and every 12 weeks during follow-up (after week 73). OS will be
monitored until death, withdrawal of consent, loss to follow-up or until the
end of the study, whichever occurs first. Radiological scans will be evaluated
according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1
at the clinical sites for treatment decisions. Independent blinded read will be
performed for primary analysis.
Intervention
IMP321 or placebo as adjunctive to standard chemotherapy with paclitaxel.
Repeated subcutaneous doses of study agent (IMP321 or placebo) will be
administered, at Day 2 (D2) and Day 16 (D16) of each 4-week cycle during the 6
cycles of weekly paclitaxel chemotherapy (chemo-immunotherapy phase). A total
of 12 SC injections of study agent will be administered during this
chemo-immunotherapy phase.
After completion of this chemo-immunotherapy phase, responding or stable
patients will receive study agent every 4 weeks during the maintenance phase
for an additional period of 48 weeks. A patient will stay on treatment until
disease progression, unacceptable toxicity, death, completion of the
maintenance phase or discontinuation for any other reason. Up to 12 further SC
injections of study agent will be administered during this phase.
Study burden and risks
The anticipated risks are based on IMP321 non-clinical and clinical experience
and are well tolerated and have an acceptable safety profile. Patients will be
monitored closely for the occurrence of any significant clinical events and
treatment will only continue if it is considered safe and appropriate to do so.
The early clinical development program of IMP321demonstrated that its use is
generally safe and well tolerated and can justify evaluation in a larger
patient population. These studies also demonstrated that IMP321 can elicit a
targeted cellular immune response and has a strong potential for anti-tumour
activity. In summary, the expected benefit definitely outweighs the expected
risks for the patients.
Rue Jean Rostand 2
Orsay 91893
FR
Rue Jean Rostand 2
Orsay 91893
FR
Listed location countries
Age
Inclusion criteria
1. Able to give written informed consent and to comply with the protocol
2.1 Metastatic oestrogen receptor positive and/or progesterone receptor
positive breast adenocarcinoma,
histologically proven by biopsy of the primary tumour and/or a metastasis
3. Female of age 18 years or above
4. Patients who are indicated to receive first line chemotherapy with weekly
paclitaxel
5.1 All patients of childbearing potential must have a negative highly
sensitive pregnancy test at
screening and agree to use highly effective method for contraception according
to the EU Clinical
Trial Facilitation Group guidance from time of study entry until at least 6
months after the last
administration of study drug. The partners of patients with childbearing
potential must also apply
contraceptive methods. Patients who are either,
o postmenopausal (>= 60 years of age, or < 60 years of age and amenorrhoeic for
12 months in the
absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression with
folliclestimulating
hormone (FSH) above 40 U/L and oestradiol below 30 ng/L; or if taking tamoxifen
or toremifene, and age < 60 years, then FSH and oestradiol in the
postmenopausal range),
permanently sterilized (e.g., bilateral tubal occlusion, hysterectomy),
o or otherwise be incapable of pregnancy are not considered to be of
childbearing potential
6. ECOG performance status 0-1
7. Expected survival longer than three months
8. Resolution of toxicity of prior therapy to grade < 2 (except for alopecia
and transaminases in case of
liver metastases)
9. Evidence of measurable disease as defined by RECIST version 1.1
10.1 Laboratory criteria:
* Total white cell count >= 3 x 10^9/L
* Platelet count >= 100 x 10^9/L
* Haemoglobin >= 9 g/dL or 5.58 mmol/L
* Absolute Neutrophil Count (ANC) >= 1.5 x 10^9/L
* Serum creatinine <= 1.5 × ULN
* Total bilirubin <= 20 µmol/L, except for familial cholaemia (Gilbert*s disease)
* Serum ASAT and ALAT <= 3 times ULN or <=5 times ULN if liver metastases are
present
Exclusion criteria
1. Prior chemotherapy for metastatic breast adenocarcinoma
2. Disease-free interval of less than twelve months from the last dose of
adjuvant chemotherapy
3. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue
4.1 Inflammatory carcinoma at time of screening
5.1 Candidate for treatment with trastuzumab (or other Her2/neu targeted
agents) or endocrine based
therapy according to the applicable treatment guidelines
6.2 Systemic chemotherapy, radiation therapy or any other investigational agent
within 4 weeks,
endocrine therapy within 1 week or CDK4/6 inhibitors within 5 times half-life
(acc. to SPC) prior
to first dose of study treatment
7.1 Symptomatic known cerebral and/or leptomeningeal metastases
8. Women who are pregnant or lactating
9. Serious intercurrent infection within 4 weeks prior to first dose of study
treatment
10. QTcF >480 ms, family or personal history of long or short QT syndrome,
Brugada syndrome or
known history of QTc prolongation, or Torsade de Pointes (TdP)
11. Uncontrolled electrolyte disorders that can worsen the effects of a
QTc-prolonging drug (e.g.,
hypocalcaemia, hypokalaemia, hypomagnesemia)
12.1 Evidence of severe or uncontrolled cardiac disease (NYHA III-IV) within 6
months prior to first
dose of study treatment including: myocardial infarction, severe/unstable
angina, ongoing cardiac
dysrhythmias of NCI CTCAE version 4.03 Grade >=2, atrial fibrillation,
coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular accident
including transient
ischemic attack, ventricular arrhythmias requiring medication or symptomatic
pulmonary embolism
13. Active acute or chronic infection
14. Active autoimmune disease requiring immunosuppressive therapy
15.1 Positive test for HIV
16.1 Positive test for Hepatitis B (anti-HBc) or C (Patients who are anti-HBc+
and HBsAg negative are eligible and are not excluded from participation in this
study)
17. Life threatening illness unrelated to cancer
18. Previous malignancies within the last three years other than breast
carcinoma, except successfully
treated squamous cell carcinoma of the skin, superficial bladder cancer, and in
situ carcinoma of the
cervix
19. Any current disorder that would impede the patient*s ability to provide
informed consent or to
comply with the protocol
20. Any condition requiring continuous systemic treatment with either
corticosteroids (>10 mg daily
prednisone equivalents) or other immunosuppressive medications within 4 weeks
prior to first dose
of study treatment. Inhaled or topical steroids and physiological replacement
doses of up to 10 mg
daily prednisone equivalent are permitted in the absence of active autoimmune
disease
21. Past history of severe allergic episodes and/ or Quincke*s oedema
22. Alcohol or substance abuse disorder
23. Known hypersensitivity to any of the components of the study agents
24.1 Participation in an interventional clinical study within 4 weeks prior to
first dose of study
treatment, with intervention not covered by exclusion criterion 6.2
25. Unwilling or unable to follow protocol requirements
26. In the clinical judgment of the Investigator, the patient is unsuitable for
participation in this study
27. Persons with any kind of dependency on the Investigator or employed by the
sponsor or Investigator
28. Persons held in an institution by legal or official order
29. Patients with prior organ or stem cell transplantation
30. Patients having received a live, attenuated vaccine within 4 weeks prior to
the first administration of
study treatment
31. Patients treated with systemic immune stimulatory agents within 6 weeks or
five half lives of the
drug prior to first administration of study treatment
Design
Recruitment
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 | EUCTR2015-002541-63-NL |
| ClinicalTrials.gov | NCT02614833 |
| CCMO | NL54895.078.15 |