A Phase I Study of IAG933 in Patients With Advanced Mesothelioma and Other Solid Tumors

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04857372

Collaborator

(none)

156

Enrollment

Locations

Arms

34.5

Anticipated Duration (Months)

15.6

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma	Drug: IAG933	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

156 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Multi-center, Phase I Study of Oral IAG933 in Adult Patients With Advanced Mesothelioma and Other Solid Tumors

Actual Study Start Date :

Oct 21, 2021

Anticipated Primary Completion Date :

Sep 6, 2024

Anticipated Study Completion Date :

Sep 6, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 Malignant pleural mesothelioma	Drug: IAG933 Capsule
Experimental: Group 2 NF2 truncating mutations or deletions	Drug: IAG933 Capsule
Experimental: Group 3 Solid tumors with functional YAP/TAZ fusions	Drug: IAG933 Capsule

Arm

Intervention/Treatment

Experimental: Group 1

Malignant pleural mesothelioma

Drug: IAG933

Capsule

Experimental: Group 2

NF2 truncating mutations or deletions

Drug: IAG933

Capsule

Experimental: Group 3

Solid tumors with functional YAP/TAZ fusions

Drug: IAG933

Capsule

Outcome Measures

Primary Outcome Measures

Number of patients with adverse events and serious adverse events [3 years]
Safety and tolerability of IAG933
Incidence of dose limiting toxicities during the first treatment cycle (dose escalation only) [1 year]
Safety, tolerability and the maximum tolerated dose or recommended dose of IAG933
Number of patients with dose interruptions and dose changes [3 years]
Tolerability of IAG933

Secondary Outcome Measures

Overall response rate (ORR) [3 years]
Assess anti-tumor activity as per RECIST v1.1 and mRECIST v1.1 (for the malignant pleural mesothelioma patients)
Disease control rate (DCR) [3 years]
Assess anti-tumor activity as per RECIST v1.1 and mRECIST v1.1 (for the malignant pleural mesothelioma)
Progression free survival (PFS) [3 years]
Assess anti-tumor activity as per RECIST v1.1 and mRECIST v1.1 (for the malignant pleural mesothelioma patients)
Duration of response (DOR) [3 years]
Assess anti-tumor activity as per RECIST v1.1 and mRECIST v1.1 (for the malignant pleural mesothelioma patients)
Overall survival (OS) (dose expansion only) [3 years]
Assess anti-tumor activity as per RECIST v1.1 and mRECIST v1.1 (for the malignant pleural mesothelioma patients)
Minimum serum concentration (Cmin) (dose escalation only) [1 year]
Characterize PK of IAG933
Maximum serum concentration (Cmax) [3 years]
Characterize PK of IAG933
Time to reach Cmax (Tmax) [3 years]
Characterize PK of IAG933
Area under the curve (AUC) [3 years]
Characterize PK of IAG933
Half life (T1/2) (dose escalation only) [1 year]
Characterize PK of IAG933
Accumulation ratio (Racc) (dose escalation only) [1 year]
Characterize PK of IAG933

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent must be obtained prior to participation in the study.
Male or female patients must be ≥ 18 years of age.
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.
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.

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.
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.

Exclusion Criteria:

Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
≤ 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.
≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
≤ 6 weeks for cytotoxic agents with risk of major delayed toxicities, such as nitrosoureas and mitomycin C.
≤ 4 weeks for immuno-oncologic therapy, such as CTLA4, PD-1, or PD-L1 antagonists
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.
Malignant disease, other than that being treated in this study.
Insufficient renal function at Screening.
Clinically significant cardiac disease or risk factors at screening
Insufficient bone marrow function at screening.
Insufficient hepatic function at screening.
Patients who have the following laboratory values outside of the laboratory normal limits:
Potassium
Magnesium
Total calcium (corrected for low serum albumin)
Known active COVID-19 infection.
Pregnant or nursing (lactating) women,
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center	Chicago	Illinois	United States	60637-1470
2	Massachusetts General Hospital Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	MD Anderson Cancer Center/University of Texas	Houston	Texas	United States	77030-4009
4	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
5	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
6	Novartis Investigative Site	Essen		Germany	45147
7	Novartis Investigative Site	Rozzano	MI	Italy	20089
8	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
9	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
10	Novartis Investigative Site	Manchester		United Kingdom	M20 4BX