A Study Evaluating the Safety and Efficacy of ENV-101 (Taladegib) in Patients With Advanced Solid Tumors Harboring PTCH1 Loss of Function Mutations

Sponsor

Endeavor Biomedicines, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05199584

Collaborator

(none)

Enrollment

Locations

Arms

23.3

Anticipated Duration (Months)

2.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study employs a 2-stage design that aims to evaluate the efficacy and safety of ENV- 101, a potent Hedgehog (Hh) pathway inhibitor, in patients with refractory advanced solid tumors characterized by loss of function (LOF) mutations in the Patched-1 (PTCH1) gene. Stage 1 of this study will enroll approximately 44 patients randomized between two dose levels. As appropriate, Stage 2 of the study will expand enrollment based on the results of Stage 1.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors With PTCH1 Loss-of-function Mutations	Drug: ENV-101 (taladegib)	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

44 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Multi-Center Study Evaluating the Safety and Efficacy of ENV-101 (Taladegib) in Patients With Advanced Solid Tumors Harboring PTCH1 Loss of Function Mutations

Actual Study Start Date :

May 24, 2022

Anticipated Primary Completion Date :

May 1, 2024

Anticipated Study Completion Date :

May 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 200 mg ENV-101 ENV-101 (taladegib) tablets, 200 mg once-daily in 28-day cycles	Drug: ENV-101 (taladegib) tablets dosed once-daily
Experimental: 300 mg ENV-101 ENV-101 (taladegib) tablets, 300 mg once-daily in 28-day cycles	Drug: ENV-101 (taladegib) tablets dosed once-daily

Arm

Intervention/Treatment

Experimental: 200 mg ENV-101

ENV-101 (taladegib) tablets, 200 mg once-daily in 28-day cycles

Drug: ENV-101 (taladegib)

tablets dosed once-daily

Experimental: 300 mg ENV-101

ENV-101 (taladegib) tablets, 300 mg once-daily in 28-day cycles

Drug: ENV-101 (taladegib)

tablets dosed once-daily

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [through study completion, an average of 6 months]
ORR is comprised of Complete Response (CR) and Partial Response (PR), measured by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1), as determined by an independent review (confirmed CR or PR will be defined as a repeat assessment performed no less than 28 days after the criteria for response is first met).

Secondary Outcome Measures

Frequency of Adverse Events (AEs) [through study completion, an average of 6 months]
Frequency of unacceptable toxicities [through study completion, an average of 6 months]
Unacceptable toxicities = non-hematologic AEs >= Grade 3 in severity, not including alopecia and fatigue.
ORR by Investigator [through study completion, an average of 6 months]
Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST 1.1.
Clinical Benefit Rate (CBR) [through study completion, an average of 6 months]
CBR = the proportion of patients who achieved CR, PR or stable disease as determined by the treating Investigator using RECIST 1.1.
Overall Survival (OS) [through study completion, an average of 6 months]
OS = Number of months from initiation of study medication to the date of death due to any cause or last follow up.
Duration of Response (DOR) [through study completion, an average of 6 months]
DOR = the number of months from the start of CR or PR, whichever response is recorded first and subsequently confirmed, to the first date that recurrent or progressive disease is documented or death.
Progression Free Survival (PFS) [through study completion, an average of 6 months]
PFS = number of months from initiation of study medication to the earlier of disease progression or death due to any cause or last follow up.
Change in Gli1 inhibition [From Baseline through study completion, an average of 6 months]
Percentage change in inhibition of Gli1, a marker for inhibition of the Hedgehog pathway, in skin biopsies.
Change in steady-state exposure to study medication [From Baseline through study completion, an average of 6 months]
Measurement of trough concentration of study medication in blood at Baseline and the end of each 28-day treatment cycle

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Females or males greater than or equal to 18 years of age. Females and males between 12 and 17 years of age (inclusive) may be enrolled if deemed appropriate after review of an X-ray with the sponsor for evaluation of growth plate development
Has histologically or cytologically confirmed solid tumor that harbors a PTCH1 loss of function mutation, identified via genomic sequencing routinely performed at a CLIA certified laboratory
Able to take medication orally
Patients must be refractory to all standard of care therapy, or standard or curative therapy does not exist, or the patient has documented their refusal of standard of care therapies
Patients willing to sign and have a full understanding of the informed consent form
Life expectancy of ≥ 3 months

Exclusion Criteria:

Concurrent administration of any anti-cancer therapies (e.g., chemotherapy, other targeted therapy) other than those administered in this study
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. Patients with indwelling catheters are allowed
Malignancies other than the primary tumor type within 5 years prior to study start, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (prior history of in situ basal or squamous cell skin cancer if completely excised, localized prostate cancer that is managed by surveillance, ductal carcinoma in situ treated surgically with curative intent are allowed)
History of clinically significant autoimmune disease requiring prescription systemic therapy in the last two years prior to study start; patients with controlled hypothyroidism may be considered after evaluation by the Investigator.
Presence of active infection at study start or confirmed active human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV)
Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to study start, unstable arrhythmias, or unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician
Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption of investigational product
Major surgical procedure within 28 days prior to study start or anticipation of need for a major surgical procedure during the course of the study
Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to study start
Use of drugs that are known moderate or stronger CYP3A4 inhibitors or inducers within 12 days prior to study start
Unresolved toxicity of ≥ CTCAE Grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, platinum-induced neurotoxicity and endocrine disease or ailments that are stable)
Males and females of reproductive potential who are sexually active and unwilling to use birth control for the duration of the study and for 30 days after their final study dose
Females that are pregnant or nursing
Females and males that are unwilling to refrain from blood or blood product donation for the duration of the study and for 30 days after their final study dose
Males who are unwilling to refrain from sperm donation for the duration of the study and for 30 days after their final study dose
Patients with a history of a severe allergic reaction, anaphylactic reaction or known hypersensitivity to any component of ENV-101
Patients who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with a study investigative site or the study Sponsor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90095
2	Research Site	San Diego	California	United States	92093
3	Research Site	Santa Monica	California	United States	90404
4	Research Site	Tampa	Florida	United States	33511
5	Research Site	Covington	Louisiana	United States	70433
6	Research Site	New York	New York	United States	10065
7	Research Site	Durham	North Carolina	United States	27710
8	Research Site	Cincinnati	Ohio	United States	45229
9	Research Site	Cleveland	Ohio	United States	44106
10	Research Site	Columbus	Ohio	United States	43210
11	Research Site	Pittsburgh	Pennsylvania	United States	15232
12	Research Site	Nashville	Tennessee	United States	37203
13	Research Site	Houston	Texas	United States	77030
14	Research Site	Fredericksburg	Virginia	United States	22408
15	Research Site	Lynchburg	Virginia	United States	24501