Immunotherapy + Chemotherapy for Sarcoma
Recruiting in Palo Alto (17 mi)
+168 other locations
Overseen bySeth M Pollack
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Steroids, Anthracyclines
Disqualifiers: Pregnancy, Interstitial lung disease, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial compares the effect of immunotherapy (pembrolizumab) plus chemotherapy (doxorubicin) to chemotherapy (doxorubicin) alone in treating patients with undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma that has spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding immunotherapy (pembrolizumab) to the standard chemotherapy (doxorubicin) may help patients with metastatic or unresectable UPS or a related poorly differentiated sarcoma live longer without having disease progression.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on daily corticosteroids, you must finish tapering off before starting the study treatment.
What data supports the effectiveness of the drug doxorubicin in treating sarcoma?
Research shows that doxorubicin is one of the most active drugs for treating sarcomas, often used in combination with other agents like ifosfamide. However, its effectiveness can be limited by resistance mechanisms, such as the activation of the insulin-like growth factor-I receptor, which can reduce the drug's ability to kill cancer cells.
12345What safety data exists for the combination of immunotherapy and chemotherapy, specifically involving doxorubicin, for sarcoma treatment?
Doxorubicin, a chemotherapy drug, is known to cause side effects like heart damage (cardiotoxicity), low white blood cell counts (myelosuppression), hair loss (alopecia), nausea, and vomiting. Liposomal formulations of doxorubicin, which are designed to reduce these side effects, have shown lower risks of heart damage and myelosuppression compared to conventional doxorubicin. However, they may increase the risk of a skin condition called palmar-plantar erythrodysesthesia (PPE).
678910What makes the combination of Doxorubicin and Pembrolizumab unique for treating sarcoma?
The combination of Doxorubicin and Pembrolizumab is unique because it pairs a standard chemotherapy drug (Doxorubicin) with an immunotherapy drug (Pembrolizumab), which has shown modest activity on its own, to potentially enhance treatment efficacy and safety in advanced soft-tissue sarcoma.
1561112Eligibility Criteria
This trial is for adults over 18 with specific aggressive sarcomas, like undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma, that have spread and can't be surgically removed. Women must have started menstruating to participate.Inclusion Criteria
My diagnosis is undifferentiated spindle cell sarcoma.
My cancer is a type of sarcoma known as myxofibrosarcoma or is poorly differentiated.
My condition is a type of sarcoma with large cells.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive doxorubicin and pembrolizumab or doxorubicin alone. Treatment repeats every 21 days for 6 cycles, with pembrolizumab continuing for up to 2 years in the absence of disease progression or unacceptable toxicity.
6 cycles (18 weeks) for doxorubicin, up to 2 years for pembrolizumab
Every 21 days
Follow-up
Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 2 years, then every 6 months for up to 10 years.
Up to 10 years
Every 3 months for 2 years, then every 6 months
Participant Groups
The study compares the effects of combining immunotherapy (pembrolizumab) with chemotherapy (doxorubicin) versus using chemotherapy alone on patients with certain advanced sarcomas to see if it improves survival without disease progression.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm A (doxorubicin and pembrolizumabExperimental Treatment6 Interventions
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
Group II: Arm B (doxorubicin)Active Control5 Interventions
Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan, standard imaging scans and blood sample collection throughout the study.
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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
Siteman Cancer Center-South CountySaint Louis, MO
Bozeman Health Deaconess HospitalBozeman, MT
Duke University Medical CenterDurham, NC
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK). [2020]Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover.
Effect of lutein and doxorubicin combinatorial therapy on S180 cell proliferation and tumor growth. [2019]Multidrug resistance and toxicity significantly compromise the therapeutic efficacy for sarcomas. We aimed at evaluating the effect of lutein-doxorubicin (DOX) combinatorial therapy on inhibiting S180 (Sarcoma 180) cell proliferation and tumor growth.
Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. [2014]More than 80% of patients with extremity sarcoma ultimately develop metastases to pulmonary sites. Doxorubicin alone or in combination with other chemotherapeutic agents may result in partial or complete tumor response for sarcoma pulmonary metastases. Regardless of the response, there has been no proven survival benefit from cytotoxic chemotherapy in the treatment of localized or metastatic soft tissue sarcoma. Insulin-like growth factor-I receptor (IGF-I-R) activation may contribute to resistance to chemotherapy in mesenchymal neoplasia. IGF-I-R activation by its ligand decreases in vitro cytotoxic response of sarcoma to doxorubicin, the most active agent against soft tissue sarcoma in adults. Furthermore, IGF-I-R is frequently overexpressed in soft tissue sarcoma and may predict poor response to traditional chemotherapy. The effect of doxorubicin on a human soft tissue sarcoma cell derived from a dedifferentiated lung metastasis was evaluated using titrated doxorubicin doses with and without exogenous IGF-I (100 ng/ml). Western blot analysis was performed to evaluate levels of phosphorylated IGF-I-R under control and experimental conditions. In vitro proliferation assays were performed. Nuclear activation through IGF-I receptor mediated pathways prior to exposing sarcoma cells to doxorubicin altered the pattern of response to doxorubicin with enhanced mitogenesis (>2-fold) and blunted doxorubicin cytotoxicity (>10% change in IC50). These data suggest that activation of IGF-I receptor in sarcoma cells is a potential mechanism for tumor resistance to doxorubicin. Inhibition of IGF-I receptor activation represents a novel approach to enhance the degree and duration of response to traditional chemotherapy against soft tissue sarcoma.
[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. [2006]Chemotherapy of sarcomas includes two major drugs: doxorubicin, ifosfamide and a third, dacarbazine, whose effectiveness remains marginal. The current challenge consists in improving the combination of these drugs, in particular by modulating their amounts. New molecules of chemotherapy show their efficiency in sarcomas. Among those, one will note above all gemcitabine and ET-743, in some sub-types. Target therapies and antiangiogenic treatment have also begun to show results. It is advisable from now on to distinguish the different sub-type of sarcomas in order to assess cytotoxic activity.
Olaratumab for the treatment of soft-tissue sarcoma. [2018]The outcome for patients with unresectable/metastatic soft tissue sarcoma remains poor with few treatment options. In the first line setting, a number of randomized trials have shown no difference in overall survival between combination anthracycline schedules and single agent doxorubicin. A Phase Ib/randomized Phase II trial of doxorubicin with or without the monoclonal antibody to PDGFR-α, olaratumab, demonstrated a significant difference in median overall survival in favor of the olaratumab arm. The results of this trial led to approval of olaratumab in combination with doxorubicin in adult anthracycline-naive unresectable soft tissue sarcoma. In this review, we describe some of the preclinical and early clinical data of olaratumab in sarcomas, the Phase Ib/II trial and ongoing trials with olaratumab in sarcomas.
Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial. [2022]Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943).
Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study. [2013]The regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) (AID) for previously untreated inoperable or metastatic sarcoma has acceptable toxicity with significant activity. Twenty patients received 79 courses of DOX (60-75 mg/m2) with or without DTIC (900 mg/m2) by continuous infusion over 72 hours with escalating doses of IFF and mesna uroprotection. Nineteen patients were evaluable for toxicity. Myelosuppression was dose-limiting. The maximum tolerated dose was DOX at 60 mg/m2, DTIC at 900 mg/m2, and IFF at 7500 mg/m2 per course. Of the 79 courses analyzed, 33 (42%) resulted in wbc counts less than 1000/microliter; 14 (18%) were complicated by fever and neutropenia, and three by sepsis. There were no toxic deaths. Relative platelet sparing was observed and nadirs were brief. In contrast to bolus-dose DTIC divided over 5 days, DTIC by continuous infusion did not add significantly to gastrointestinal toxicity. Nausea and vomiting was well controlled by antiemetics. Mucositis occurred sporadically. Unlike our phase II study of IFF alone, no CNS or renal toxicity was observed. No cardiac toxicity was encountered, although only four patients have received greater than 450 mg/m2 of cumulative DOX. One episode of DOX extravasation occurred despite a long iv line that extended to the axilla. No serious tissue damage was observed, perhaps due to the dilute solutions of DOX used. Partial responses were seen in eight of 18 evaluable patients (44%) and in six of 11 patients at or near the phase II level. Two additional patients with minimal response have continued tumor regression. The median number of courses before partial response was four (range, one to five). The median duration of response has not been reached (3+ to 10+ months). An inoperable primary has been rendered surgically resectable in one patient. Activity in previously untreated sarcomas should be further evaluated in a randomized phase III study against a standard DOX-containing combination.
Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure. [2022]Doxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma.
Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity.
Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]Doxorubicin (DOX) is an anthracycline widely used for the treatment of solid and hematological tumors. The aim of this study was to assess the adverse event profiles of conventional DOX and liposomal DOX. This is the first study to evaluate the effect of a liposomal formulation of DOX using spontaneous reporting system (SRS) databases. The SRS used was the US Food and Drug Administration Adverse Event Reporting System (FAERS). This study relied on definitions of preferred terms provided by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ) database. We also calculated the reporting odds ratios (RORs) of suspected drugs (conventional DOX; PEGylated-liposome DOX; non-PEGylated-liposome DOX). The FAERS database contained 7,561,254 reports from January 2004 to December 2015. The number of reported AE cases for conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX was 5039, 3780, and 349, respectively. Conventional DOX and liposomal DOX have potential risks of causing myelosuppression, cardiotoxicity, alopecia, nausea, and vomiting, among other effects. The RORs (95% CI) from SMQ for haematopoietic leucopenia associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 12.75 (11.89-13.68), 6.43 (5.81-7.13), and 14.73 (11.42-18.99), respectively. Liposomal DOX formulations were associated with lower RORs with regard to myelosuppression, cardiotoxicity, and alopecia than the conventional DOX was. The RORs (95% CI) for palmar-plantar erythrodysesthesia (PPE) associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 6.56 (4.74-9.07), 64.77 (56.84-73.80), and 28.76 (15.77-52.45), respectively. This study is the first to evaluate the relationship between DOX liposomal formulations and their adverse event profiles. The results indicate that careful observation for PPE is recommended with the use of liposomal DOX, especially PEGylated-liposome DOX formulations.
Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. [2022]Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS.
Paclitaxel (Taxol) plus doxorubicin plus filgrastim in advanced sarcoma: a phase II study. [2019]The authors evaluated the novel chemotherapeutic regimen of paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ, U.S.A.) plus doxorubicin plus filgrastim--a granulocyte colony-stimulating factor (G-CSF)--in advanced or metastatic sarcoma. Eligible patients must have had histologically confirmed advanced previously untreated soft-tissue sarcoma. All patients must have had bidimensionally measurable metastases. Treatment consisted of doxorubicin, 50 mg/m2 by intravenous push, followed 4 hours later by paclitaxel, 150 mg/m2 by continuous infusion over 24 hours every 3 weeks, plus G-CSF, 5 microg/kg, on days 3 through 12 of each cycle. Cycles were repeated every 21 days. A one-time dose escalation for doxorubicin only (60 mg/m2) was allowed in all patients who experienced no significant toxicity after their first cycle of paclitaxel plus doxorubicin. From November 1993 through May 1996, 29 patients were entered in this study. Grade 3 anemia occurred in three patients. Grade 3--4 neutropenia occurred in 20 patients. Seven patients experienced at least one episode of neutropenic fever, including one death. Grade 3 thrombocytopenia occurred in four patients. There were six partial responses in 27 eligible patients, for a response rate of 22.2% (95% confidence interval, 7%-38%). Median time to progression was 4.5 months, and median overall survival was 10.2 months. The regimen of paclitaxel plus doxorubicin plus filgrastim as used in this study appears to have no more activity than single-agent doxorubicin.