Ontorpacept + Doxorubicin for Leiomyosarcoma

(TTI-621-03 Trial)

Recruiting at 31 trial locations

Overseen By Pfizer CT.gov Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Trillium Therapeutics Inc.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Heart failure, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 14

Duration: 18 weeks

76 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effects of a new medicine, Ontorpacept, both alone and combined with doxorubicin (a chemotherapy drug), for treating leiomyosarcoma. Leiomyosarcoma is a cancer affecting smooth muscles that can spread to other body parts. The trial targets individuals whose cancer has advanced or spread and who have had no more than one previous treatment. Participants will initially receive both Ontorpacept and doxorubicin, then continue with just Ontorpacept to assess the combination's effectiveness. This study suits those who haven't been treated with anthracyclines, a common cancer drug. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you were treated with a prior chemotherapy regimen, you must have completed it at least three weeks before starting the study treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that adding Ontorpacept (also known as TTI-621) to doxorubicin showed a promising safety profile for patients with advanced leiomyosarcoma, indicating that the combination was generally well-tolerated. Researchers observed that while some side effects occurred, most were manageable for patients.

Doxorubicin, a drug commonly used in cancer treatments, has a well-known safety profile. Ontorpacept, however, is still under study to fully understand its effects. Early research suggests that when combined with doxorubicin, Ontorpacept does not cause unexpected or severe side effects beyond those typically associated with cancer treatment.

This trial is in an advanced phase, indicating that earlier stages have shown the treatment to be relatively safe. Participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ontorpacept (TTI-621) combined with doxorubicin for treating leiomyosarcoma because it introduces a novel approach to tackling this aggressive cancer. Unlike standard treatments, which typically focus on chemotherapy alone, Ontorpacept is designed to block CD47, a "don't eat me" signal used by cancer cells to evade the immune system. By targeting CD47, Ontorpacept allows the body's immune cells to recognize and attack the cancer more effectively. This combination could potentially enhance the effectiveness of traditional chemotherapy, offering new hope for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for leiomyosarcoma?

Research has shown that Ontorpacept (also known as TTI-621) might enhance the effectiveness of doxorubicin, a common cancer drug, in treating leiomyosarcoma. This trial will explore different dose levels of Ontorpacept combined with fixed-dose doxorubicin, followed by Ontorpacept monotherapy, to assess safety, tolerability, and clinical activity. Early studies suggest that TTI-621 can help the body's immune system fight tumors in leiomyosarcoma by targeting a protein called CD47 on cancer cells, which usually helps them hide from the immune system. By blocking CD47, TTI-621 allows immune cells to attack the tumor more effectively. Although more research is needed, initial results indicate that these treatments together could benefit patients with this challenging cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

This trial is for people with advanced leiomyosarcoma, a type of muscle tumor, who haven't been treated with anthracyclines and have had at most one other treatment. Participants should be in good overall health with no severe allergies to antibodies or history of certain autoimmune diseases or organ transplants.

Inclusion Criteria

Adequate organ and hematologic function

Patients who were treated with a prior chemotherapy regimen must have completed treatment at least three weeks before initiation of study treatment

All adverse events from prior treatment must be NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) v5 Grade ≤ 1, except alopecia and stable neuropathy, which must have resolved to Grade ≤ 2 or baseline

Exclusion Criteria

You have received treatment with a specific type of medication called anti-CD47 or anti-SIRPα therapy before.

You have a history of serious heart problems.

You have or have had serious heart problems that affect how well your heart pumps blood.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive doxorubicin and Ontorpacept (TTI-621) for 18 weeks, with doxorubicin administered every 3 weeks and Ontorpacept administered weekly.

18 weeks

12 visits (in-person)

Monotherapy

Participants continue receiving Ontorpacept (TTI-621) every 14 days until disease progression.

Until disease progression

Every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• TTI-621

Trial Overview The study tests Ontorpacept (TTI-621) alone and combined with Doxorubicin in treating leiomyosarcoma. Initially, both drugs are given by IV every three weeks for 18 weeks; afterwards, only Ontorpacept is continued biweekly until it's not effective anymore.

How Is the Trial Designed?

Group I: Dose Expansion Dose Level C (Cohort C) Experimental Treatment 2 Interventions

Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level C) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen.

Group II: Dose Expansion Dose Level B (Cohort B) Experimental Treatment 2 Interventions

Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level B) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen.

Group III: Dose Expansion Dose Level A (Cohort A) Experimental Treatment 2 Interventions

Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level A) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen.

Group IV: Dose Escalation (Ontorpacept+doxorubicin) Experimental Treatment 2 Interventions

In the dose escalation portion of the study, participants with specific subsets of soft tissue sarcomas who have not received more than one prior line of therapy and have not received an anthracycline in any setting will be enrolled in three escalating dose cohorts to characterize the safety and tolerability of Ontorpacept (TTI-621) when administered in combination with doxorubicin for up to six cycles and followed by Ontorpacept (TTI-621) monotherapy

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

Trillium Therapeutics Inc.

Lead Sponsor

Trials

7

Recruited

620+

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, indicating limited efficacy in this specific patient population.

Despite the lack of effectiveness, Doxil was well tolerated, with no grade 4 toxicities and only a few instances of grade 3 toxicities, suggesting a favorable safety profile for future studies in different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Garcia, AA., Kempf, RA., Rogers, M., et al.[2022]

In a phase II study involving 35 patients with advanced uterine leiomyosarcomas, liposomal doxorubicin showed limited efficacy, with only 1 complete response and 4 partial responses, indicating it may not be more effective than traditional doxorubicin.

The treatment was associated with significant toxicity, including grade 3 or 4 neutropenia in 16.1% of patients and gastrointestinal issues in several cases, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Sutton, G., Blessing, J., Hanjani, P., et al.[2022]

Lutein combined with doxorubicin (DOX) significantly inhibited the proliferation of S180 sarcoma cells in vitro, leading to increased cell apoptosis and reduced expression of growth-related proteins, indicating a potential mechanism for enhanced anti-cancer effects.

In vivo studies showed that the lutein-DOX combination therapy not only reduced tumor growth and size more effectively than DOX alone but also decreased the cytotoxicity and inflammatory response associated with DOX, suggesting a safer therapeutic option for sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of lutein and doxorubicin combinatorial therapy on S180 cell proliferation and tumor growth. Luan, RL., Wang, PC., Yan, MX., et al.[2019]

The proposed generic doxorubicin hydrochloride liposome injection (SPIL) demonstrated comparable antitumor efficacy to the reference product (Caelyx) in mouse models, significantly reducing tumor volume without significant differences in effectiveness at any tested dose.

Both SPIL and the reference injection exhibited similar toxicity profiles and pharmacokinetics, confirming their bioequivalence and supporting the development of affordable cancer treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipodox® (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx® (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. Burade, V., Bhowmick, S., Maiti, K., et al.[2018]

Probucol pretreatment significantly increased the clearance of doxorubicin (DOX) in plasma and altered its distribution in various tissues, suggesting it affects the pharmacokinetics of DOX.

Probucol also provided cardioprotection against DOX-induced toxicity by improving the ATP/ADP ratio and reducing markers of heart damage, indicating its potential as a protective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. El-Demerdash, E., Ali, AA., Sayed-Ahmed, MM., et al.[2013]

Doxorubicin (DOX) is effective for treating childhood cancers but can cause heart damage, and while Dexrazoxane (DXR) is a known cardioprotectant, Amifostine (AMF) also shows protective properties but may negatively impact bone health.

In a study with female rats, treatments involving AMF, with or without DOX and DXR, led to significant decreases in bone mineral density and deterioration of bone microarchitecture, highlighting the need for careful consideration in cancer treatment combinations to avoid bone damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. Mwale, F., Ciobanu, I., Demers, CN., et al.[2013]

The combination of paclitaxel and doxorubicin has significantly improved clinical outcomes for breast cancer patients, particularly in neoadjuvant settings for locally advanced cases.

However, this combination therapy is associated with cardiac toxicity, highlighting the need for careful monitoring and future research to mitigate these risks while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. Ferrero, JM., Magné, N., Foa, C., et al.[2015]

Doxorubicin (DOX) is a powerful chemotherapy drug, but it can cause serious heart damage (cardiotoxicity), which limits its use in treating solid tumors.

Research has identified several natural products and herb extracts that may help reduce DOX-induced heart damage without compromising its cancer-fighting ability, but more studies are needed to confirm their effectiveness in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. Yu, J., Wang, C., Kong, Q., et al.[2018]

Electrospray manufacturing of Myocet-like liposomes allows for a more efficient and scalable production process, enhancing drug retention and stability compared to traditional thin-film hydration methods.

The electrosprayed liposomes demonstrated similar drug loading and cytotoxicity profiles to conventional formulations, but with significantly prolonged release kinetics, potentially improving therapeutic outcomes for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrosprayed Myocet-like Liposomes: An Alternative to Traditional Liposome Production. Collier, MA., Bachelder, EM., Ainslie, KM.[2018]

In a phase II study involving 33 patients with malignant pleural mesothelioma, Caelyx (a liposomal form of doxorubicin) was found to be well tolerated, with mild toxicity primarily manifesting as palmar plantar erythrodysesthesia in 62% of patients.

Despite being well tolerated, Caelyx showed limited efficacy, with only 6% of patients achieving a partial response and a median survival of 13 months, indicating that it may not be a promising single-agent treatment for chemotherapy-naive mesothelioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caelyx in malignant mesothelioma: a phase II EORTC study. Baas, P., van Meerbeeck, J., Groen, H., et al.[2020]

In a phase II trial involving 40 women with recurrent Müllerian malignancies, the combination of liposomal doxorubicin and paclitaxel showed an overall objective response rate of 29%, with a higher response rate of 54% in patients whose tumors recurred at least 6 months after platinum-based therapy.

The combination treatment was associated with increased skin toxicity, specifically palmar plantar erythrodysesthesia, but did not affect the pharmacokinetics of paclitaxel, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of liposomal doxorubicin and weekly paclitaxel for recurrent Müllerian tumors. Campos, SM., Matulonis, UA., Penson, RT., et al.[2019]

In a trial involving 94 patients with advanced soft-tissue sarcoma, CAELYX (pegylated liposomal doxorubicin) demonstrated a significantly lower incidence of severe myelosuppression and alopecia compared to standard doxorubicin, indicating a better safety profile.

Both CAELYX and doxorubicin showed similar antitumor activity, with response rates of 10% and 9% respectively, suggesting that CAELYX is a viable alternative for treatment with reduced toxicity, warranting further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Judson, I., Radford, JA., Harris, M., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04996004

NCT04996004 | A Study to Learn About the ... The purpose of this study is to learn about the safety and effects of the study medicine (called Ontorpacept or TTI-621) when given alone and when given in ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.11508

Safety and clinical activity of TTI-621 in combination with ... Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10031121/

Therapeutic advances in leiomyosarcoma - PMC Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas.

4. withpower.com withpower.com/trial/phase-2-leiomyosarcoma-5-2021-6efcf

Ontorpacept + Doxorubicin for Leiomyosarcoma (TTI-621 ... In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, ...

5. researchgate.net researchgate.net/publication/367696850_TTI-621-03_A_phase_III_study_of_TTI-621_in_combination_with_doxorubicin_in_patients_with_unresectable_or_metastatic_high-grade_leiomyosarcoma_LMS

A phase I/II study of TTI-621 in combination with ... The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04996004/

Clinical Trial: NCT04996004 Phase I (Dose Escalation of TTI-621 in combination with doxorubicin) will enroll patients with soft-tissue sarcomas including leiomyosarcoma, ...

7. researchgate.net researchgate.net/publication/371301121_Safety_and_clinical_activity_of_TTI-621_in_combination_with_doxorubicin_in_patients_with_unresectable_or_metastatic_high-grade_leiomyosarcoma_Results_from_the_low-dose_expansion_cohort

Safety and clinical activity of TTI-621 in combination with ... Preclinical studies suggest TTI-621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as leiomyosarcoma (LMS). A phase 1 ...