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

• ClinicalTrials.gov Identifier: NCT04857372
• Recruitment Status: Recruiting
• First Posted: April 23, 2021
• Last Update Posted: March 6, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 20, 2021
• First Posted Date: April 23, 2021
• Last Update Posted Date: March 6, 2023
• Actual Study Start Date: October 21, 2021
• Estimated Primary Completion Date: September 6, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 20, 2021)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 20, 2021)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mesothelioma

Intervention

Drug: IAG933

Capsule

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 20, 2021): 156
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 6, 2024
• Estimated Primary Completion Date: September 6, 2024 (Final data collection date for primary outcome measure)

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.

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.

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 chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
   3. ≤ 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 outside of the laboratory normal limits:

   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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

• Listed Location Countries: Australia, Canada, France, Germany, Italy, Japan, Netherlands, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT04857372
• Other Study ID Numbers: CIAG933A12101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: March 2023