ATI-2231 With in Advanced Solid Tumor Malignancies Followed by ATI-2231 in Combination With Capecitabine in Patients With Hormone Receptor-positive and HER2 Negative Metastatic Breast Cancer

Sponsor

Washington University School of Medicine (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05791474

Collaborator

United States Department of Defense (U.S. Fed), Aclaris Therapeutics, Inc. (Industry)

174

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase Ia is a dose-escalation Phase I study of ATI-2231 monotherapy, using 3 plus 3 design, with the primary endpoint of adverse events. Phase Ib tests the safety and tolerability of ATI-2231 in combination with chemotherapy (capecitabine) at recommended phase II dose (RP2D) obtained from Phase Ia. This is followed by the randomized Phase II study of ATI-2231 in combination with chemotherapy testing the hypothesis that the combination of chemotherapy (capecitabine) and ATI-2231 will reduce bone turnover, improve clinical efficacy including progression-free survival (PFS), improve patient bone density and patient quality of life.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: ATI-2231 Drug: Capecitabine Drug: Denosumab Drug: Bisphosphonate	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

174 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Trial of ATI-2231 With Phase Ia in Advanced Solid Tumor Malignancies Followed by Phase Ib/II in Combination With Capecitabine in Patients With Hormone Receptor-positive and HER2 Negative Metastatic Breast Cancer

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2030

Anticipated Study Completion Date :

Oct 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase Ia: ATI-2231 monotherapy dose escalation Patients with advanced solid tumor malignancies are eligible. Patients will receive single agent ATI-2231 at assigned dose levels (n=3-6 per dose level). Starting dose of 20 mg by mouth twice per day. From one dose level to the other dose will not exceed two fold. Final decision on dose level for each dose escalation will be made by the investigator, with input from the safety review committee. Each cycle is 21 days	Drug: ATI-2231 Provided by Aclaris Therapeutics, Inc.
Experimental: Phase Ib: ATI-2231 + capecitabine Patients with advanced hormone receptor-positive (HR+)/HER2-negative breast cancer with or without bone metastasis are eligible. Patients will receive ATI-2231 (by mouth twice per day) at the monotherapy recommended Phase 2 dose plus capecitabine at standard dose. Two dose levels (RP2D-L1 and RP2D-L2) of ATI-2231 will be tested, starting with RP2D-L1 (n=6 patients per dose level). Capecitabine dose will be 1000 mg/m^2 by mouth twice per day of Days 1-14 of each 21 day cycle.	Drug: ATI-2231 Provided by Aclaris Therapeutics, Inc. Drug: Capecitabine Commercially available
Experimental: Phase II Arm 1: ATI-2231 dose level 1 plus capecitabine Patients with advanced HR+/HER2-negative breast cancer with progressing bone metastasis are eligible. Patients will receive ATI-2231 (by mouth twice daily) dose level 1 plus capecitabine. Capecitabine dose will be 1000 mg/m^2 by mouth twice per day of Days 1-14 of each 21 day cycle.	Drug: ATI-2231 Provided by Aclaris Therapeutics, Inc. Drug: Capecitabine Commercially available
Experimental: Phase II Arm 2: ATI-2231 dose level 2 plus capecitabine Patients with advanced HR+/HER2-negative breast cancer with progressing bone metastasis are eligible. Patients will receive ATI-2231 (by mouth twice daily) dose level 2 plus capecitabine. Capecitabine dose will be 1000 mg/m^2 by mouth twice per day of Days 1-14 of each 21 day cycle.	Drug: ATI-2231 Provided by Aclaris Therapeutics, Inc. Drug: Capecitabine Commercially available
Active Comparator: Phase II Arm 3: Standard of care: antiresorptive agents + capecitabine Patients with advanced HR+/HER2-negative breast cancer with progressing bone metastasis are eligible. Patients will receive standard of care anti-resportive agents (denosumab or zoledronic acid) plus capecitabine.	Drug: Capecitabine Commercially available Drug: Denosumab Commercially available Drug: Bisphosphonate Commercially available

Outcome Measures

Primary Outcome Measures

Number of participants experiencing adverse events (Phase Ia and Phase Ib ONLY) [From baseline through 30 days after end of treatment (estimated to be 11 months)]
-Graded per CTCAE v. 5.0
Percentage reduction in serum C-terminal telopeptide (CTX) (Phase II ONLY) [Baseline and Day 1 of Week 7]
Progression-free survival (PFS) (Phase II ONLY) [Through completion of follow-up (estimated to be 46 months)]
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Secondary Outcome Measures

Changes in ATI-2231 pharmacokinetics (PK) as measured by time to peak drug concentration (Tmax) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 day 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by elimination rate constant (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 day 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by apparent volume of distribution (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 day 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by apparent clearance (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 day 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by peak concentration (Cmax) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 day 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by half-life (T1/2) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by area under the curve (AUC0-24h) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, and 24 hours post dose cycle 1 (estimated to be 1 day)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by area under the curve (AUC0-infinity) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by area under the curve (AUC0-t) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 1 day 1, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 24 hours, 30 hours, and 48 hours post dose cycle 1 (estimated to be 2 days)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by peak concentration (Cmax) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 2 day 1 (each cycle is 21 days), 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours post dose cycle 2 day 1 (estimated to be 10 hours)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by trough concentration (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 2 day 1 (each cycle is 21 days), 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours post dose cycle 2 day 1 (estimated to be 10 hours)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by area under the curve (AUC0-t) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 2 day 1 (each cycle is 21 days), 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours post dose cycle 2 day 1 (estimated to be 10 hours)]
Changes in ATI-2231 pharmacokinetics (PK) as measured by time to peak drug concentration (Tmax) (Phase Ia and Phase Ib ONLY) [Pre-dose cycle 2 day 1 (each cycle is 21 days), 1 hour, 2 hours, 4 hours, 6 hours, and 10 hours post dose cycle 2 day 1 (estimated to be 10 hours)]
ATI-2231 pharmacokinetics (PK) as measured by trough concentration (Phase Ia and Phase Ib ONLY) [Cycle 3 day 1 (each cycle is 21 days)]
ATI-2231 pharmacokinetics (PK) as measured by trough concentration (Phase Ia and Phase Ib ONLY) [Cycle 4 day 1 (each cycle is 21 days)]
ATI-2231 pharmacokinetics (PK) as measured by trough concentration (Phase Ia and Phase Ib ONLY) [Cycle 5 day 1 (each cycle is 21 days)]
ATI-2231 pharmacokinetics (PK) as measured by trough concentration (Phase Ia and Phase Ib ONLY) [Cycle 6 day 1 (each cycle is 21 days)]
Treatment induced changes in bone mineral density (BMD) (Phase Ia and Phase Ib ONLY) [Pre-treatment, after 8 cycles (each cycle is 21 days) or at the time of progression if it occurs within 8 cycles]
- Measured using DEXA BMD at hip and spine
Treatment induced changes in serum C-terminal telopeptide (CTX) levels as assessed by clinical assay (Phase II ONLY) [Baseline and Day 1 of Week 7]
Treatment induced changes in bone turnover markers (BTMs) as measured by levels of P1NP (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in bone turnover markers (BTMs) as measured by levels of osteocalcin (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in bone turnover markers (BTMs) as measured by levels of bone-specific alkaline phosphatase (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in bone turnover markers (BTMs) as measured by levels of betaCTx (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in bone turnover markers (BTMs) as measured by levels of TRAP (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in inflammatory cytokines as measured by TNF-α (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in inflammatory cytokines as measured by IL-1β (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in inflammatory cytokines as measured by IL-6 (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Treatment induced changes in inflammatory cytokines as measured by IL-10 (Phase II ONLY) [Baseline, Cycle 1 Day 8 (each cycle is 21 days), Cycle 1 Day 15 (each cycle is 21 days), Day 1 of each subsequent cycle (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
Objective response rate (ORR) (Phase II ONLY) [Through completion of treatment (estimated to be 10 months)]
ORR = number of patients with complete response or partial response Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Clinical benefit rate (CBR) (Phase II ONLY) [Through completion of treatment (estimated to be 10 months)]
-CBR = percentage of evaluable patients who had complete response, partial response, or stable disease for at least 24 weeks
Overall survival (OS) (Phase II ONLY) [Through completion of follow-up (estimated to be 46 months)]
-OS = time from the start of the study treatment to time of death or last follow-up if alive
Number of participants experiencing adverse events (Phase II ONLY) [From baseline through 30 days after end of treatment (estimated to be 11 months)]
Treatment induced changes in bone mineral density (Phase II ONLY) [Pre-treatment, after 8 cycles (each cycle is 21 days) or at the time of progression if it occurs within 8 cycles]
-Measured using DEXA BMD at hip and spine
Change in quality of life as measured by EORTC-QLC-C30 (Phase II ONLY) [Pre-treatment, cycle 5 day 1 (each cycle is 21 days), every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
-The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0) is a questionnaire designed to assess the quality of life of cancer patients. It is a core questionnaire associated with a broad range of cancer-specific modules, including breast cancer modules EORTC QLQ-BR23. The QLQ-C30 is composed of five functional scales, three symptom scales, a global health status/QoL scale and six single items. All of the scales and single-item measures range in score from 0 to 100. A high score of functional scale, symptom scales and global health status/QoL scale corresponds to a high/healthy level of functioning, high level of symptomatology/problems, and high QoL, respectively.
Change in bone pain as measured by Brief Pain Inventory (BPI) (Phase II ONLY) [Pre-treatment, Cycle 5 Day 1 (each cycle is 21 days), every 4 cycles thereafter (each cycle is 21 days), and at the time of progression (estimated to be 10 months)]
-Brief pain inventory (BPI) rapidly assesses the severity of pain and its impact on daily functioning. It assesses the severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week. The total score is 0-110. A higher score represents worse pain.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Phase Ia: Biopsy-proven advanced solid tumor malignancy with refractory disease.
Phase Ib: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with or without bone metastasis by current ASCO/CAP guidelines.
Phase II: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with progressive bone metastasis per the latest tumor imaging studies.
Measurable or non-measurable but evaluable disease by RECIST v 1.1.
No more than one prior chemotherapy for metastatic disease (Phase 1b and Phase II only). There are no limits on prior endocrine therapy-based regimens.

Note: History of trastuzumab deruxtecan treatment is not a required inclusion criteria as this drug is currently approved in HER2-low metastatic breast cancer following one line of chemotherapy in the metastatic setting.

Phase Ib: Planning to start or on stable doses of capecitabine (capecitabine cohort: no less than 1000 mg/m2 BID, 14 days on and 7 days off)
Phase II: Candidate for initiating capecitabine treatment per physician decision and history of prior endocrine therapy with CDK4/6 inhibitor.
At least 4 weeks have passed (i.e., washout period of 4 weeks is required) with denosumab and zoledronic acid, before the start of study treatment if the patient was on these drugs before enrollment, including patients in the Phase II study.
At least 6 months of therapy with bisphosphonate or denosumab for bone metastasis is required in patients who received these agents prior to enrolling to the Phase II study only.
Phase Ib: Washout from prior chemotherapy other than capecitabine (for the capecitabine cohort) for 3 weeks or passed 5 half-lives and recovered adverse events (AEs) to Grade 1 (except for alopecia).
Phase II: Washout from prior chemotherapy for 3 weeks or passed 5 half-lives and recovered AEs to Grade 1 (except for alopecia).
A washout period of 1 week is required from the completion of radiation therapy.
At least 18 years of age.
ECOG performance status ≤ 2
Life expectancy of at least 12 weeks.
Adequate bone marrow and organ function as defined below:
Leukocytes ≥ 3,000/mcL
Absolute neutrophil count (ANC) ≥ 1,500/mcL
Platelets ≥ 100,000/mcL
Total bilirubin ≤ 1.5 x IULN
AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
Creatinine clearance > 60 mL/min by Cockcroft-Gault
The effects of ATI-2231on the developing human fetus are unknown. For this reason, women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 1 month (for women) or 3 months (for men) after the end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease (Phase II only).
Currently receiving any other investigational agents.
Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids or on stable/decreasing steroid dose.
A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ATI-2231 or other agents used in the study.
History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC antiresorptive agents after entering the study (Phase II only).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
Patients with known HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kansas University Medical Center	Kansas City	Kansas	United States	66160
2	Mayo Clinic	Rochester	Minnesota	United States	55905
3	Washington University School of Medicine	Saint Louis	Missouri	United States	63110