A Study of HST-1011 For The Treatment Of People With Advanced Cancers That Are Not Benefiting From Other Standard of Care Therapies

Phase 1/2

Completed

• Conditions: Advanced Solid Tumors

• Registration Number: 2023-503731-18-00
• Lead Sponsor: Hotspot Therapeutics Inc.

Brief Summary

- A1: To characterize the initial safety and tolerability of HST-1011 as monotherapy

- A2: To determine the Recommended Phase 2 Dose (RP2D) and schedule of HST-1011 monotherapy in patients with select tumor types

- B1: To characterize the initial safety and tolerability profile of HST-1011 administered in combination with cemiplimab

- B2: To determine the Recommended Phase 2 Dose (RP2D) and schedule of HST-1011 in combination with cemiplimab in patients with select tumor types

Detailed Description

Not available

Study Timeline

• Study First Posted: 2023-10-19
• Last Update Posted: 2025-04-09

Recruitment & Eligibility

• Status: Ended
• Sex: Not specified
• Target Recruitment: 20

Inclusion Criteria

Phase 1 Parts A1, A2, B1, B2:

9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening and prior to dosing on C1D1.

10. Female patients: If of childbearing potential: • Must have a negative serum pregnancy test within 14 days prior to the first dose of study drug C1D1 AND • If heterosexually active, must commit to using 2 highly effective forms of birth control (Appendix 5) and must not donate oocytes for the duration of the study and for 4 months following the last dose of HST-1011. For Part B1 and Part B2, where patients will receive a combination of HST-1011 and cemiplimab, birth control and prohibition of oocyte. ....

11. Male patients: • If heterosexually active with a partner of child-bearing potential as defined in inclusion criteria #10, must commit to the use of a highly effective method of birth control (Appendix 5) and not donate sperm for the duration of the study and for 4 months following the last dose of HST-1011 or for 6 months following the last dose of cemiplimab OR • Must be sterile (biologically or surgically)

12. Patient’s last dose of previous systemic anticancer therapy or major surgery must be ≥ 21 days prior to the first dose of HST-1011 or the last dose of therapy with a small molecule therapy must be either ≥ 5 times the half-life of the therapy OR ≥ 21 days prior to the first dose of study treatment, whichever is shorter. Note that gonadal suppression or endocrine therapy for patients with prostate cancer, a prior breast or ovarian cancer, or an elevated genetic risk of specific cancers should be discussed with the Sponsor Medical Monitor as these medications may be permitted on a patient-by-patient basis.

13. Patient has stopped taking all strong and moderate CYP3A4 inhibitors and inducers and proton pump inhibitors (except pantoprazole which is allowed on study) (Appendix 8) within 14 days prior to onset of HST-1011 treatment, with prior discussion with the Sponsor Medical Monitor required for approval of any exceptions. If patient requires a proton pump inhibitor, they must be switched to pantoprazole prior to onset of HST-1011 treatment to be eligible.

14. Patient has had all prior anticancer therapy toxicities resolve to ≤ Grade 1 at the time of Screening with the following exceptions: • Alopecia • Ongoing toxicities attributed to systemic prior anticancer therapy or palliative radiation which are not expected to resolve and which result in long lasting sequelae (eg neuropathy or ototoxicity after platinum-based therapy) • Endocrinopathies from prior immunotherapy as long as patient is stable on an adequate replacement therapy

15. Patient has a life expectancy > 12 weeks in the opinion of the Investigator.

16. Patient is at least 18 years of age.

17. Patient is capable of understanding and complying with protocol requirements.

18. Patient has signed and dated an institutional review board/independent ethics committee (IRB/IEC) approved informed consent form (ICF) before any protocol-directed screening procedures are performed.

19. Patient has a histologically confirmed advanced solid tumor (metastatic, recurrent and/or unresectable) in 1 of the following categories: a. Patient with tumor types where anti-PD-(L)1 therapies are approved, meeting one of the below criteria: • Patient must be anti-PD-(L)1 relapsed / refractory defined as having clear evidence of radiologic or clinical progression while on or within 4 months of their last anti-PD-(L)1 dose OR • Patient must have had stable disease for at least 6 months while on active anti-PD-(L)1 therapy (Kluger et al, 2020) and have evidence of tumor growth or clinical deterioration and/or their physician believes starting treatment with HST-1011 is in their best interest. OR  Patient must have non-small cell lung cancer with a known oncogenic driver mutation (EGFR) or fusion (ALK, ROS1) that is relapsed/ refractory to approved standard-of-care targeted therapies but has not yet received chemotherapy / anti- PD-(L)1 and their physician believes starting treatment with HST-1011 is in their best interest. b. Patient with one of the following tumor types in which anti-PD-(L)1 therapies are not approved and patient may thus be naïve to prior anti-PD-(L)1 agents: • Platinum-resistant ovarian (including fallopian and primary peritoneal) cancer • Locally advanced or metastatic prostate cancer with no more than one prior line of chemotherapy, unless discussed directly with Sponsor Medical Monitor for approval • Anal cancer • Rectal cancer (Note: this would include patients with microsatellite stable disease, as patients with high microsatellite instability would be eligible following approved PD-(L)1 therapy, as per sub-bullet a).

20. Patient has failed prior standard of care therapies appropriate for their metastatic disease and has had no more than 1 intervening systemic therapy since their last failed anti-PD-(L)1 therapeutic regimen, unless discussed directly with Sponsor Medical Monitor for approval. Patients with actionable mutations must have failed targeted therapies approved as a standard of care for those mutations.

21. Patient has at least 1 measurable non-central nervous system (CNS) lesions per RECIST version 1.1 that can be safely biopsied, unless discussed directly with Sponsor Medical Monitor for approval.

22. Patient has provided consent for pre- and on-treatment biopsies, unless in the Investigator’s opinion it is not medically feasible to biopsy and this has been discussed directly with the Sponsor Medical Monitor for approval. Note: Patients enrolled in Part A1 single patient cohorts are not required to provide biopsies.

23. Patient has adequate organ function as defined in the following table, with discussion with Sponsor Medical Monitor required for any exceptions due to patients who may have baseline laboratory values that have minor and clinically insignificant fluctuations

Exclusion Criteria

1. Patient has active autoimmune disease or other medical conditions (eg, active interstitial lung disease/pneumonitis or eczema, psoriasis, or other clinically significant dermatologic disorders) requiring chronic systemic steroid (> 10 mg/day prednisone or equivalent) or immunosuppressive therapy within 6 months prior to first administration of study treatment (unless agreed otherwise between the Medical Monitor and the Investigator on a case-by-case basis). Non-systemic corticosteroids (eg, topical, inhaled) or short-term, symptom-focused use of systemic corticosteroids are allowed.

2. Patient has received live vaccines within 4 weeks of first HST-1011 dose (Note: Any vaccines that do not contain live viruses are permitted).

3. Patient has a history of a seizure within 6 months of Screening. For patients with a seizure secondary to a discrete medical event (eg metastatic disease in the CNS within 6 months of screening or a traumatic brain injury) eligibility will be determined following a discussion with the Sponsor Medical Monitor.

4. Patient has had an unacceptable intolerance to prior anti-PD-(L)1 monoclonal antibody therapy (Part B1 and Part B2 only).

5. Patient has known or suspected active infection with SARS-CoV-2 virus.

6. Patient has any other systemic conditions or organ abnormalities that, in the opinion of the Investigator, may interfere with the conduct and/or interpretation of the current study.

7. Patient has 1 or more of the following: a. Unstable angina b. Myocardial infarction within 6 months prior to screening c. New York Heart Associate Class II or greater congestive heart failure d. QT interval corrected using Fredericia’s formula (QTcF) ≥470 msec obtained from the mean of 3 consecutive resting ECGs unless a patient has underlying cardiac conduction abnormalities in which an alternative correction method should be used to accurately document QTc. In this case, the alternative approach must be discussed with Sponsor Medical Monitor for approval. e. Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG f. Congenital long QT syndrome g. Uncontrolled hypertension

8. Patient has previously participated in a clinical study evaluating a CBL-B inhibitor.

9. Patient is a pregnant or lactating female.

10. Patient has received prior systemic chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 21 days or 5 half-lives (if known), whichever is shorter, before receiving their first dose of HST-1011. Note that gonadal suppression or endocrine therapy for patients with prostate cancer, a prior breast or ovarian cancer, or an elevated genetic risk of specific cancers should be discussed with the Sponsor Medical Monitor as these medications may be permitted on a patient-by-patient basis.

11. Patient has received radiotherapy within 14 days of their first dose of HST-1011, unless discussed with Sponsor’s Medical Monitor for approval.

12. Patient is currently taking any concomitant medications at Screening that have the potential to cause a clinically relevant drug-drug interaction with HST-1011, unless discussed with Sponsor’s Medical Monitor.

13. Patient has untreated and/or symptomatic metastatic CNS disease. Note: Patients with brain/CNS metastases who have undergone surgery or radiotherapy, whose disease is stable and who have been on a stable, low dose of corticosteroids (≤ 10 mg prednisone or equivalent) for at least 4 weeks prior to the first dose of HST-1011 will be eligible.

14. Patient has had a stroke or transient ischemic attack within 6 months prior to Screening, unless discussed with Sponsor Medical Monitor for approval.

15. Patient has a known allergy or hypersensitivity to any of the excipients used in the oral formulation of HST-1011 capsules, or any known allergy or hypersensitivity to cemiplimab (for Part B1 and B2 only).

16. Patient has history of an allergy causing anaphylaxis, unless discussed with Sponsor Medical Monitor for approval.

17. Patient has history of mast cell activation syndrome or mastocytosis, unless discussed with Sponsor Medical Monitor for approval.

18. Patient has history of hereditary angioedema.

19. Patient with a history of gastrointestinal disease that may affect absorption of the study drug, or patients who are not able to take oral medications.

20. Patient with a history of prior allogenic tissue/solid organ transplant.

21. Patient has any medical condition that in the opinion of the Investigator would prevent the patient’s full participation in the clinical study due to safety or compliance with study procedures.

22. Patient has any other known, active malignancy. Note: Patients with localized cancers that do not require chronic systemic treatment with a low chance of recurrence after definitive therapy are permissible after discussion with the Sponsor Medical Monitor.

23. Patient has a known active uncontrolled hepatitis B, hepatitis C, or HIV infection. Patients whose viral load is controlled should be on established antiretroviral therapy for at least 4 weeks prior to receiving their first dose of study drug. Note: Patients who test positive for anti-HCV Ab but negative for HCV ribonucleic acid (RNA) are considered eligible. Patients who are HbsAg+ and have a DNA load of <2000 IU/mL or HbcAb+ and have an RNA load of <2000 IU/mL (104 copies/mL) are considered eligible.

24. Patient has an active infection requiring systemic therapy, not including the viruses mentioned in exclusion criterion 16.

25. Patient has any unresolved toxicities from prior therapy greater than Grade 1 at the time of starting study drug with the exception of alopecia, expected long term sequalae from prior therapy, or endocrinopathies from prior immunotherapy with patient now on stable replacement therapy.

Study & Design

• Study Type: Not specified
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
A1: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams.		A1: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams.
B1: Incidence of DLTs, TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams		B1: Incidence of DLTs, TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
B2: Integration of safety, PDc, PK, and preliminary efficacy endpoints		B2: Integration of safety, PDc, PK, and preliminary efficacy endpoints
A2: Integration of safety, PDc, PK, and preliminary efficacy endpoints		A2: Integration of safety, PDc, PK, and preliminary efficacy endpoints

Secondary Outcome Measures

Name	Time	Method
A1: PK parameters including but not limited to: maximum observed plasma concentration (Cmax), time of maximum observed plasma concentration (Tmax), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUC0-t) or in 1 dosing interval (AUCtau), concentration observed at trough (Ctrough, Ctau)		A1: PK parameters including but not limited to: maximum observed plasma concentration (Cmax), time of maximum observed plasma concentration (Tmax), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUC0-t) or in 1 dosing interval (AUCtau), concentration observed at trough (Ctrough, Ctau)
A1: Summary measures of HST-1011 PK parameters after oral administration		A1: Summary measures of HST-1011 PK parameters after oral administration
A1: ORR per Investigator assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1		A1: ORR per Investigator assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
A1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles		A1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles
A2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams		A2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
A2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)		A2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)
B1: PK parameters including but not limited to: Cmax, Tmax, AUC0-t, AUCtau, Ctrough, Ctau		B1: PK parameters including but not limited to: Cmax, Tmax, AUC0-t, AUCtau, Ctrough, Ctau
B1: Summary measures of HST-1011 PK parameters after oral administration		B1: Summary measures of HST-1011 PK parameters after oral administration
B1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles		B1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles
B1: ORR per Investigator assessed RECIST v1.1		B1: ORR per Investigator assessed RECIST v1.1
B2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams		B2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
B2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)		B2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)
B2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles		B2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles
A2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable		A2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable
B2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable		B2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable
A2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles		A2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles

Trial Locations

Locations (3)

Clinica Universidad De Navarra; 🇪🇸 Pamplona, Spain

Hospital Universitario Quironsalud Madrid; 🇪🇸 Pozuelo De Alarcon, Spain

Hospital Quironsalud Barcelona; 🇪🇸 Barcelona, Spain

Clinica Universidad De Navarra

🇪🇸Pamplona, Spain

Ignacio Melero

Site contact

+34948255400

imelero@unav.es