Clinical trial NCT04857372: A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors
Official title: An Open-label, Multi-center, Phase I Study of Oral IAG933 in Adult Patients With Advanced Mesothelioma and Other Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Mesothelioma
Keywords: Mesothelioma
IAG933
NF2 mutated tumors
LATS1/LATS2 mutated tumors
YAP/TAZ
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-04-23
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors with functional YAP/TAZ fusions and to identify the maximum tolerated dose and/or recommended dose.

Detailed description: This is a phase I, open-label, multi-center study of IAG933 as a single agent consisting of a dose escalation part, followed by a dose expansion part. The escalation part will characterize the safety and tolerability. After the determination of the recommended dose/maximum tolerated dose, dose expansion will assess the preliminary anti-tumor activity in defined patient populations and further assess the safety and tolerability at RD/MTD.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients must be ≥ 18 years of age.
3. Dose escalation part: patients with histologically or cytologically confirmed diagnosis of advanced (unresectable or metastatic) mesothelioma or other solid tumors. Patients with solid tumors other than mesothelioma must have local available data for loss-of-function NF2/LATS1/LATS2 genetic alterations (truncating mutation or gene deletion; LATS1/LATS2 mutations will only be included in the dose escalation part), or functional YAP/TAZ fusions. Patients with malignant EHE can be enrolled with only histological confirmation of the disease. Patients must have failed available standard therapies, be intolerant of or ineligible for standard therapy, or for whom no standard therapy exists.
4. Dose expansion part: the following patients will be enrolled into 3 different treatment groups:

   Group 1: Advanced (unresectable or metastatic) MPM patients who have failed available standard therapies for advanced/metastatic disease, be intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.

   Group 2: Advanced (unresectable or metastatic) solid tumor patients with available local data for NF2 truncating mutation or deletions. Patient must have failed available standard therapies, be intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.

   Group 3: Advanced (unresectable or metastatic) solid tumor patients with available local data for functional YAP/TAZ fusions. EHE patients can be included with only histological confirmation of the disease. Patient must have failed available standard therapies, be intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.

   Group 4: Advanced (unresectable or metastatic) non-pleural mesothelioma patients who have failed available standard therapies for advanced/metastatic disease, are intolerant or ineligible to receive such therapy, or for whom no standard therapy exists.
5. Presence of at least one measurable lesion according to mRECIST v1.1 for mesothelioma patients, RECIST v1.1 for patients with other solid tumors, or RANO for patients with primary brain tumors.
6. Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/baseline, and again during therapy on this study. An archival tumor sample may be used at screening. During the dose expansion part of the study, a decision may be made to stop the collection of on-treatment biopsies.

Exclusion Criteria:

1. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:

   1. ≤ 4 weeks for thoracic radiotherapy to lung fields or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment. An exception to this exists for patients who have received palliative radiotherapy to bone, who must have recovered from radiotherapy-related toxicities but for whom a 2-week washout period is not required.
   2. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
   3. ≤3 weeks for treatment with cytotoxic agents or ≤ 6 weeks for cytotoxic agents with risk of major delayed toxicities, such as nitrosoureas and mitomycin C.
   4. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA4, PD-1, or PD-L1 antagonists
   5. Prior treatment with TEAD inhibitor at any time
2. For mesothelioma patients: use of non-invasive antineoplastic therapy (e.g., tumor treating fields, brand name Optune LuaTM) within 2 weeks of the tumor assessment at screening.
3. Malignant disease, other than that being treated in this study.
4. Insufficient renal function at Screening.
5. Clinically significant cardiac disease or risk factors at screening
6. Insufficient bone marrow function at screening.
7. Insufficient hepatic function at screening.
8. Patients who have the following laboratory values \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1:

   1. Potassium
   2. Magnesium
   3. Total calcium (corrected for low serum albumin)
9. Known active COVID-19 infection.
10. Pregnant or nursing (lactating) women,
11. Japan only: patients with a history of drug- and/or non-drug-induced interstitial lung disease (ILD) ≥ Grade 2.

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Number of patients with adverse events and serious adverse events
timeFrame: 3 years
measure: Incidence of dose limiting toxicities during the first treatment cycle (dose escalation only)
timeFrame: 1 year
measure: Number of patients with dose interruptions and dose changes
timeFrame: 3 years
Secondary outcomes:
measure: Overall response rate (ORR)
timeFrame: 3 years
measure: Disease control rate (DCR)
timeFrame: 3 years
measure: Progression free survival (PFS)
timeFrame: 3 years
measure: Duration of response (DOR)
timeFrame: 3 years
measure: Overall survival (OS) (dose expansion only)
timeFrame: 3 years
measure: Minimum serum concentration (Cmin) (dose escalation only)
timeFrame: 1 year
measure: Maximum serum concentration (Cmax)
timeFrame: 3 years
measure: Time to reach Cmax (Tmax)
timeFrame: 3 years
measure: Area under the curve (AUC)
timeFrame: 3 years
measure: Half life (T1/2) (dose escalation only)
timeFrame: 1 year
measure: Accumulation ratio (Racc) (dose escalation only)
timeFrame: 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: Chicago
country: United States
facility: Uni of Chi Medi Ctr Hema and Onco
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel CCC At JH
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Massachusetts General Hospital
state: Massachusetts
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References: