- To assess the safety and tolerability and to determine the RP2D of T-DXd plus durvalumab in combination with cisplatin, carboplatin or pemetrexed
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To assess the safety and tolerability and to determine the RP2D of T-DXd plus
durvalumab in combination with cisplatin, carboplatin or pemetrexed
Secondary outcome
- To assess the preliminary antitumor activity of T-DXd monotherapy (Part 1
only); T-DXd with durvalumab (Part 2 only); and T-DXd plus durvalumab in
combination with cisplatin, carboplatin or pemetrexed
- To assess the safety and tolerability of T-DXd montherapy (Part 1) and T-DXd
plus durvalumab (Part 2)
- To assess the PK of T-DXd, total anti-HER2 antibody and MAAA-1181 in all arms
- To assess the PK of durvalumab
- To investigate the immunogenicity of T-DXd and durvalumab
Background summary
The standard treatment for patients with metastatic NSCLC (mNSCLC) is currently
based on molecularly characterization of a defined subset. Platinum doublet
chemotherapy with anti-PD-1/PD-L1 targeting immunotherapy is the current
standard of care for mNSCLC without EGFR or ALK genomic tumor aberrations.
Among patients with a tumor proportion score for PD-L1 of 50% or greater,
pembrolizumab is considered a first line treatment of choice. However, there is
a significant patient population emerging that does not respond to PD-1 or
PD-L1 containing therapy or progresses during anti-PD-1/PD-L1 containing
therapy.
Her2 expression is identified as therapeutic target in several tumor types. In
a phase I trial (NCT02564900) trastuzumab deruxtecan has shown anti-tumor
activity in several tumor types expressing HER2, including NSCLC.
Given the encouraging response in this study, further investigation in patients
with non-small cell lung cancer and an unmet medical need is warranted.
Study objective
- To assess the safety and tolerability and to determine the RP2D of T-DXd plus
durvalumab in combination with cisplatin, carboplatin or pemetrexed
Study design
This is a phase Ib multicenter open-label dose escalation study to evaluate the
safety and tolerability of Trastuzumab Deruxtecan (T-DXd) and Durvalumab in
combination with cisplatin, carboplatin or pemetrexed in first-line treatment
of patients with advanced or metastatic non-squamous non-small cell lung cancer
(NSCLC) and human epidermal growth factor receptor 2 overexpression (HER2+).
The study consists of 2 parts:
- Part 1: dose-escalation combinations and fixed dose T-DXd monotherapy
treatment in patients eligible for second or third-line therapy, and
- Part 2: dose-expansion treatment for patients to receive first-line treatment
Part 1 Dose-escalation Combinations and T-DXd Monotherapy:
Patients in Part 1 may receive:
Arm 1A: Cisplatin combination
- Cisplatin: ascending dose levels (60 mg/m2 [staring dose], 75 mg/m2): IV Q3W,
plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1B: Carboplatin combination
- Carboplatin: ascending dose levels (AUC 4 [staring dose], AUC 5): IV Q3W, plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1C: Pemetrexed combination
- Pemetrexed: ascending dose levels (375 mg/m2 [staring dose], 500 mg/m2): IV
Q3W, plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1D: T-DXd monotherapy
- T-DXd: fixed dose (5.4 mg/kg) IV Q3W
The dose of T-DXd and chemotherapeutic components on Arms 1A, 1B and 1C will be
modified during the Dose Escalation Phase according to figure 1 of CSP v3,
dated 30 April 2021 in order to find the recommended phase 2 dose.
Approximately, 18 patients will be included per treatment arm. A maximum of 48
patients may be enrolled per arm.
Part 2: Dose Expansion
Dose expansions for Arms 1A, 1B and 1C may be initiated after the
dose-escalation part. For dose expansions, approximately 30 patients (maximum
of 33) will be assigned treatment per dose level.
Patients will continue to receive treatment until any discontinuation criteria
are met, including RECIST v1.1 objective disease progression, withdrawal of
consent, or investigator determination that the patient is no longer benefiting
from study intervention.
Intervention
Part 1: Dose Escalation Combinations and T-DXd Monotherapy
Arm 1A: Cisplatin combination
- Cisplatin: ascending dose levels (60 mg/ml2 [starting dose], 75 mg/ml2): IV
Q3W, plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1B: Carboplatin combination
- Carboplatin: ascending dose levels (AUC 4 [staring dose], AUC 5): IV Q3W, plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1C: Pemetrexed combination
- Pemetrexed: ascending dose levels (375 mg/m2 [staring dose], 500 mg/m2): IV
Q3W, plus
- T-DXd: ascending dose levels (3,2 mg/kg, 4,4 mg/kg [starting dose], 5,4
mg/kg) IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Arm 1D: T-DXd monotherapy
- T-DXd: fixed dose 5,4 mg/kg IV Q3W
Part 2: Dose Expansion:
Arm 2A, 2B and 2C:
- will initiate after RP2D is identified from Part 1
Arm 2D:
- T-DXd: 5,4 mg/kg IV Q3W, plus
- Durvalumab: fixed dose (1120 mg): IV Q3W
Study burden and risks
Patients have to visit the hospital more often and the visits will take longer.
Patients may have to stay overnight at the hospital on the day that patients
receive the first administration of treatment.
On several days during the study, patients will undergo the following
assessments:
- Anamnesis (inclusive medical history)
- Pulmonary function test
- ECHO/MUGA scan (LVEF)
- Eye assessment
- ECG
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate,
SpO2)
- At home pulse oximetry
- Length and weight
- ECOG performance status
- Physical examination
- Blood- and urine examination
- Questionnaires (MDASI, SGRQ-I)
- Pregnancy test (if applicable)
- AE/SAE
- CT/MRI at screening and every 6 weeks thereafter
- CT chest at screening and if ILD/pneumonitis is suspected
- Administration study medication
- Biopsy at screening (if no or not sufficient tumor tissue is present) and at
progression (optional)
Study medication can also cause adverse events:
Adverse events trastuzumab deruxtecan: serious adverse events may include ILD,
heart problems, allergic reactions and infusion related reactions.
The following adverse events are very common (>= 10%):
- Nausea
- Feeling tired (Fatigue)
- Vomiting
- Hair loss (Alopecia)
- Constipation
- Feeling less hungry
- Decrease in the number of red blood cells (Anemia)
- Decrease in the number of neutrophils (Neutropenia)
- Diarrhea
- Decrease in the number of platelets (Thrombocytopenia)
- Coughing
- Decrease in the number of white blood cells (Leukopenia)
- Stomach (abdominal) pain
- Infections of the upper respiratory tract
- Headache
- Indigestion (Dyspepsia)
- Dizziness
- Sores in or around your mouth (Stomatitis)
- Difficulty breathing (Dyspnea)
- Severe nose bleeds (Epistaxis)
- Lung problems (Interstitial Lung Disease)
- Coughing with phlegm, fever, chills (pneumonia)
- Low potassium in the blood (Hypokalemia)
- Decrease in number of lymphocytes (Lymphopenia)
- Blood tests showing increased level of liver enzymes such as transaminases
- Pain in muscles and bone
- Weight loss
- Fever (Pyrexia)
- Swelling of lower legs or hands (Edema peripheral)
- Bad taste in mouth (dysgeusia)
Adverse events durvalumab (very common (>=10%):
- Diarrhea
- Rash / dry itching skin
- Abdominal pain
- Upper respiratory tract infections
- Cough
- Fever
- Underactive thyroid gland that can cause tiredness or weight gain
(hypothyroidism)
Chemotherapy can also cause adverse events.
Also study procedures can cause adverse events:
- Pain or bruising due to blood draw
- Rash due to patches of ECG
- Health risks due to radiation of CT scan or MRI
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
- Histologically documented stage III locally advanced/metastatic and
unresectable non-squamous NSCLC not amenable to curative surgery or radiation
and/or stage IV NSCLC
- Part 1 (dose-escalation combinations and T-DXd monotherapy): Patients with
therapy-targetable alterations are allowed.
- Part 2 (dose-expansion): Tumors that lack activating EGFR mutations or
EML4-ALK fusion
- Part 1 (dose-escalation combinations and T-DXd monotherapy): Progression on
or after either one or 2 lines of therapy which is required to have included
prior appropriate targeted therapy for patients with therapy-targetable
alterations.
- Part 2 (dose-expansion): treatment-naïve for locally advanced or mNSCLC.
Prior adjuvant, neo adjuvant therapies are permitted if progression has
occurred > 12 months from the end of last therapy
- HER2+ (IHC 3+ or 2+) status as determined by central review of tumor tissue
- WHO / ECOG performance status of 0 or 1
- Has a measurable target disease assessed by the investigator using RECIST 1.1
- Has a protocol defined adequate organ and bone marrow functions
Exclusion criteria
- Has a history of (non-infectious) ILD/pneumonitis that required steroids, has
current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out
by imaging at screening
- Lung criteria:
* Specific intercurrent clinically significant illnesses including, but not
limited to, any underlying pulmonary disorder
* Any auto-immune, connective tissue or inflammatory disorders (eg. Rheumatoid
arthritis, Sjogren*s syndrome, sarcoidosis etc) where this is documented, or a
suspicion of pulmonary involvement at the time of screening.
* Prior pneumonectomy (complete)
- Active primary immunodeficiency known HIV infection, or active hepatitis B or
C infection
- Active infection including tuberculosis and uncontrolled infection requiring
IV antibiotics, antivirals, or antifungals
- Spinal cord compression or clinically active central nervous system
metastases, defined as untreated and symptomatic, or requiring therapy with
corticosteroids or anticonvulsants to control associated symptoms
- Medical history of myocardial infarction within 6 months before treatment
assignment, symptomatic CHF (New York Heart Association Class II to IV),
clinically important cardiac arrhythmias, or a recent (<6 months)
cardiovascular event including stroke
- A pleural effusion, ascites or pericardial effusion that requires drainage,
peritoneal shunt, or CART
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 | EUCTR2020-003260-31-NL |
| ClinicalTrials.gov | NCT04686305 |
| CCMO | NL75431.056.21 |