Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer

• ClinicalTrials.gov Identifier: NCT05384119
• Recruitment Status: Recruiting
• First Posted: May 20, 2022
• Last Update Posted: August 8, 2023
• Sponsor: Tvardi Therapeutics, Incorporated
• Information provided by (Responsible Party): Tvardi Therapeutics, Incorporated

Study Description

Brief Summary:

The primary objective of Phase 1b will be to evaluate the safety and tolerability of TTI-101 when added to palbociclib and AI or fulvestrant administered orally to participants with hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2)- palbociclib-resistant breast cancer, and to determine the recommended Phase 2 dose (RP2D) for TTI-101 when added to palbociclib and AI or fulvestrant.

The primary objective of Phase 2 will be to evaluate anti-tumor activity in participants who receive TTI-101 added to palbociclib or ribociclib and AI or fulvestrant.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: TTI-101; Drug: Palbociclib; Drug: Aromatase inhibitor (AI); Drug: fulvestrant; Drug: ribociclib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 53 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: REVERT- Breast Cancer: Phase 1b/2 Study of the Addition of STAT3 Inhibitor TTI-101 to Reverse Resistance to Palbociclib or Ribociclib Plus Aromatase Inhibitor or Fulvestrant Therapy for Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer
• Actual Study Start Date: January 9, 2023
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: February 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1b: Dose Escalation; Participants will receive up to 3 dose levels of TTI-101 added to palbociclib and AI or fulvestrant to determine the RP2D.	Drug: TTI-101; Oral tablet; Drug: Palbociclib; Oral capsule; Other Name: Ibrance ®; Drug: Aromatase inhibitor (AI); Oral tablet; Drug: fulvestrant; Oral tablet
Experimental: Phase 2: Dose Expansion; Enrollment in Phase 2 may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101 added to palbociclib or ribociclib and AI or fulvestrant.	Drug: TTI-101; Oral tablet; Drug: Palbociclib; Oral capsule; Other Name: Ibrance ®; Drug: Aromatase inhibitor (AI); Oral tablet; Drug: fulvestrant; Oral tablet; Drug: ribociclib; Oral tablet

Outcome Measures

Primary Outcome Measures :

1. Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT) [ Time Frame: Day 1 to Day 28 ]
2. Phase 1b: Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 18 months ]
   An AE is any untoward medical occurrence in a participant or clinical study participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Any clinically significant changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs and physical examinations will be recorded as AEs.
3. Phase 1b: Number of Participants Who Experience a Serious Adverse Event (SAE) [ Time Frame: Up to approximately 18 months ]
4. Phase 2: Landmark Progression Free Sulrvival at 6 Months (PFS6) [ Time Frame: Day 1 pre-dose and 6 months post-dose ]

Secondary Outcome Measures :

1. Phase 1b: PFS6 [ Time Frame: Day 1 pre-dose and 6 months post-dose ]
2. Phase 1b and Phase 2: Clinical Benefit Rate (CBR) [ Time Frame: Up to approximately 18 months ]
   Defined as complete response (CR) + partial response (PR) + stable disease (SD) for at least 6 months.
3. Phase 1b and Phase 2: Overall Response Rate (ORR) [ Time Frame: Up to approximately 18 months ]
   Defined as complete response (CR) + partial response (PR) measured in all participants using RECIST Version 1.1.
4. Phase 1b and Phase 2: Overall Response Rate (ORR) [ Time Frame: Up to approximately 18 months ]
   Defined as complete response (CR) + partial response (PR) measured using RECIST Version 1.1 in participants who have a follow-up on-study tumor assessment at least 42 days following Cycle 1 Day 1 (cycle is 28 days) and who receive at least 80% of scheduled dosing with TTI-101.
5. Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of TTI-101 [ Time Frame: Cycle 2 Day 1 (cycle is 28 days) ]
6. Phase 1b and Phase 2: Time of Maximum Observed Plasma Concentration (Tmax) of TTI-101 [ Time Frame: Cycle 2 Day 1 (cycle is 28 days) ]
7. Phase 1b and Phase 2: Area Under the Plasma Concentration-time Curve from Time 0 to Time t (AUC[0-t]) of TTI-101 [ Time Frame: Cycle 2 Day 1 (cycle is 28 days) ]
8. Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 1 (pY-STAT1) Positive Cells in Tumor Biopsy Samples [ Time Frame: Baseline to Cycle 3 Day 1 (cycle is 28 days) ]
9. Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 3 (pY-STAT3) Positive Cells in Tumor Biopsy Samples [ Time Frame: Baseline to Cycle 3 Day 1 (cycle is 28 days) ]
10. Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 5 (pY-STAT5) Positive Cells in Tumor Biopsy Samples [ Time Frame: Baseline to Cycle 3 Day 1 (cycle is 28 days) ]
11. Phase 1b and Phase 2: Duration of Response (DoR) to Treatment [ Time Frame: Up to approximately 18 months ]
12. Phase 1b and Phase 2: Time to Tumor Progression (TTP) [ Time Frame: Up to approximately 18 months ]
13. Phase 1b and Phase 2: Best Overall Response (BOR) [ Time Frame: Up to approximately 18 months ]
14. Phase 1b and Phase 2: Progression-free Survival (PFS) [ Time Frame: Up to approximately 18 months ]
15. Phase 1b and Phase 2: Progression-free Survival (PFS) at 6 Months [ Time Frame: Up to approximately 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Participants must meet all the following criteria to be eligible:

1. Age ≥18 years at the time of informed consent.
2. Metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.

3. For Phase 1b,currently receiving palbociclib and AI or fulvestrant; for Phase 2, currently receiving palbociclib or ribociclib and AI or fulvistrant therapy in the metastatic setting with evidence of progressive disease. In addition:

   • Must have remained on palbociclib or ribociclib and AI or fulvestrant therapy for ≥6 months for advanced breast cancer or metastatic disease prior to evidence of progression that in the opinion of the treating physician warrants continued therapy with palbociclib or ribociclib and AI or fulvestrant.
   • Dosage of palbociclib, ribociclib, AI and fulvestrant must remain unchanged from regimen prior to study enrollment specifically palbociclib at a dose of 125, 100, or 75 mg administered orally for 21 days every 28-day cycle or ribociclib at a dose of 200, 400, or 600 mg administered orally for 21 days every 28-day cycle.
4. All men and premenopausal women must be on medical gonadal suppression therapy with a gonadotropin analog (e.g, goserelin or leuprolide) and have estrogen levels in the postmenopausal range by institutional criteria at baseline.
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Has documented confirmation of histological or cytological HR-positive, HER2-negative breast cancer per local laboratory testing.
7. Up to 2 prior lines of systemic treatment (most recent line of therapy must be palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2) in the locally advanced or metastatic setting is allowed; the participant must have shown evidence of progressive disease on palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2 in the locally advanced or metastatic setting prior to enrollment.
8. Willing to provide a representative fresh tumor tissue specimen prior to enrollment. The fresh tumor specimen must be obtained after evidence of progression on palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2.

9. The presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 is required. Lesions in a previously irradiated area that have not progressed are not considered measurable.

   • Participants with bone only disease WITHOUT a soft tissue component, may opt out of the tumor biopsy.

10. The presence of measurable disease as per RECIST Version 1.1 is preferred but not required. Lesions in a previously irradiated area that have not progressed are not considered measurable.

Exclusion Criteria:

Participants meeting any of the following exclusion criteria will not be eligible:

1. Has received more than 2 lines of prior systemic therapy for locally advanced/metastatic breast cancer.
2. Had prior exposure to any signal transducer and activator of transcription 3 (STAT3) inhibitor.
3. Had radiotherapy within 3 weeks prior to Cycle 1 Day 1 (cycle is 28 days). Participants must have recovered from radiotherapy toxicities prior to starting study treatment and recovered to Grade 1 or better from related side effects of such therapy (with the exception of alopecia).
4. Has HER2 overexpression by local laboratory testing (immunohistochemical [IHC] 3+ or in situ hybridization positive).
5. Has known loss of retinoblastoma tumor suppressor gene (Rb) or estrogen receptor 1 (ESR1) activating mutation (testing not mandatory).
6. Has had disease progression on more than two cyclin-dependent kinase (CDK)4/6 inhibitors. Adjuvant abemaciclib is allowed but must have progressed on palbociclib or ribociclib.
7. Concurrently using other anticancer therapy. Participants must continue palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2.

Contacts and Locations

Contacts

Contact: Kari Anne Rowland, MS; Please email; info@tvardi.com

Contact: Sofia de Achaval, PhD; Please email; info@tvardi.com

Locations

United States, Florida

Holy Cross Health Fort Lauderdale - Holy Cross Hospital; Recruiting

Fort Lauderdale, Florida, United States, 33308

Contact: Eileen Georgi, MSN, RN 954-267-7748

United States, Missouri

Washington University School of Medicine Siteman Cancer Center; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Cynthia X Ma, M.D., Ph.D. 314-273-3978 cynthiaxma@wustl.edu

United States, Ohio

Gabrail Cancer Center Research; Recruiting

Canton, Ohio, United States, 44718

Contact: Kimberly Roby 330-492-3345 ext 227 GCCResearch@gabrailcancercenter.com

United States, Texas

Harold C. Simmons Comprehensive Cancer Center; Recruiting

Dallas, Texas, United States, 75390

University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Debasish Tripathy, M.D. 713-792-2817

Sponsors and Collaborators

Tvardi Therapeutics, Incorporated

More Information

• Responsible Party: Tvardi Therapeutics, Incorporated
• ClinicalTrials.gov Identifier: NCT05384119
• Other Study ID Numbers: TVD-101-002B
• First Posted: May 20, 2022
• Last Update Posted: August 8, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Tvardi Therapeutics, Incorporated:

Breast cancer; HR+ HER2-, palbociclib-resistant breast cancer; TTI-101; STAT3 Inhibitor; Palbociclib; Aromatase inhibitor; ribociclib; fulvestrant

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Fulvestrant; Palbociclib; Aromatase Inhibitors; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors