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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hotspot Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Sep 2024 → 31 Oct 2025

Decision date (initial)

2023-10-19

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

HotSpot Therapeutics, Inc.

External identifiers

EU CT number

2023-503731-18-00

ClinicalTrials.gov

NCT05662397

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Efficacy, Dose response, Safety

- 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

Secondary objectives 14

1. A1: To characterize the pharmacokinetics (PK) of HST-1011 following oral administration of HST-1011 monotherapy
2. A1: To determine the preliminary objective response rate (ORR) of HST-1011
3. A1: To evaluate the effects of HST-1011 monotherapy on select peripheral pharmacodynamic (PDc) markers
4. A2: To further characterize the safety and tolerability profile of HST-1011
5. A2: To further characterize the PK of HST-1011
6. A2: To further evaluate the effects of HST-1011 monotherapy on various PDc markers in blood
7. A2: To further characterize preliminary antitumor activity of HST-1011 monotherapy
8. B1: To characterize the PK of HST-1011 administered in combination with cemiplimab
9. B1: To evaluate the effects of HST-1011 administered in combination with cemiplimab on select peripheral PDc markers
10. B1: To determine the preliminary ORR of HST-1011 in combination with cemiplimab
11. B2: To further characterize the safety and tolerability profile of HST-1011 in combination with cemiplimab
12. B2: To further characterize the PK of HST-1011 in combination with cemiplimab
13. B2: To further evaluate the effects of HST-1011 in combination with cemiplimab on various PDc markers in blood
14. B2: To further characterize preliminary antitumor activity of HST-1011 in combination with cemiplimab

Conditions and MedDRA coding

Advanced Solid Tumors

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Phase 1 Parts A1, A2, B1, B2:
2. 1. Patient is at least 18 years of age.
3. 2. Patient is capable of understanding and complying with protocol requirements.
4. 3. 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.
5. 4. 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).
6. 5. 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.
7. 6. 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.
8. 7. 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.
9. 8. 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
10. 9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening and prior to dosing on C1D1.
11. 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. ....
12. 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)
13. 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.
14. 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.
15. 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
16. 15. Patient has a life expectancy > 12 weeks in the opinion of the Investigator.

Exclusion criteria 25

1. 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. 10. 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.
3. 11. 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.
4. 12. Patient with a history of prior allogenic tissue/solid organ transplant.
5. 13. 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.
6. 15. 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.
7. 16. 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.
8. 17. Patient has an active infection requiring systemic therapy, not including the viruses mentioned in exclusion criterion 16.
9. 18. 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.
10. 19. Patient has received live vaccines within 4 weeks of first HST-1011 dose (Note: Any vaccines that do not contain live viruses are permitted).
11. 20. 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.
12. 2. Patient has had an unacceptable intolerance to prior anti-PD-(L)1 monoclonal antibody therapy (Part B1 and Part B2 only).
13. 21. Patient has known or suspected active infection with SARS-CoV-2 virus.
14. 22. 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.
15. 3. 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
16. 4. Patient has previously participated in a clinical study evaluating a CBL-B inhibitor.
17. 5. Patient is a pregnant or lactating female.
18. 6. 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.
19. 7. Patient has received radiotherapy within 14 days of their first dose of HST-1011, unless discussed with Sponsor’s Medical Monitor for approval.
20. 8. 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.
21. 9. Patient has had a stroke or transient ischemic attack within 6 months prior to Screening, unless discussed with Sponsor Medical Monitor for approval.
22. 14. 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).
23. 23. Patient has history of an allergy causing anaphylaxis, unless discussed with Sponsor Medical Monitor for approval.
24. 24. Patient has history of mast cell activation syndrome or mastocytosis, unless discussed with Sponsor Medical Monitor for approval.
25. 25. Patient has history of hereditary angioedema.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 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.
2. A2: Integration of safety, PDc, PK, and preliminary efficacy endpoints
3. B1: Incidence of DLTs, TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
4. B2: Integration of safety, PDc, PK, and preliminary efficacy endpoints

Secondary endpoints 16

1. 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)
2. A1: Summary measures of HST-1011 PK parameters after oral administration
3. A1: ORR per Investigator assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
4. A1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles
5. A2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
6. A2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)
7. A2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles
8. B1: PK parameters including but not limited to: Cmax, Tmax, AUC0-t, AUCtau, Ctrough, Ctau
9. B1: Summary measures of HST-1011 PK parameters after oral administration
10. B1: Peripheral blood cytokines / chemokines and changes in global gene expression profiles
11. B1: ORR per Investigator assessed RECIST v1.1
12. B2: Incidence of TEAEs, SAEs, and changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs, and physical exams
13. B2: Summary measures of HST-1011 PK parameters after oral administration (single and multiple dose)
14. B2: Peripheral blood cytokines / chemokines, immune cell numbers and phenotypes, and changes in global gene expression profiles
15. A2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable
16. B2: Investigator assessed: ORR, DOR, DCR, PFS and OS per RECIST v1.1 or PCWG3 criteria, as applicable

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hotspot Therapeutics Inc.

Sponsor organisation

Hotspot Therapeutics Inc.

Address

50 Milk Street Floor 16th

City

Boston

Postcode

02109-5002

Country

United States

Scientific contact point

Organisation

Hotspot Therapeutics Inc.

Contact name

HotSpot Therapeutics, Head of Clinical Development

Public contact point

Organisation

Hotspot Therapeutics Inc.

Contact name

HotSpot Therapeutics, Head of Clinical Development

Third parties 8

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications