Neoplasms

All Conditions

Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Participants will receive pembrolizumab IV infusion and doxorubicin IV injection on Day 1 of every 21 (+/- 3) days

IV infusion on day 1 of each 3 week cycle, at dose of 200 mg

IV injection on day 1 of each 3 week cycle, starting at dose of 60 mg/m2 (may be escalated to 75 mg/m2 per investigator discretion after Cycle 1)

Megan Jagosky, MD

The purpose of this study is to evaluate the safety, tolerability and efficacy of doxorubicin in combination with pembrolizumab in subjects with metastatic or unresectable soft tissue sarcoma. Based on previous studies, pembrolizumab may be an effective study treatment.

The primary objective of this study is to assess the safety and toxicity profile of doxorubicin and pembrolizumab in previously treated or untreated subjects with unresectable or metastatic soft tissue sarcoma. The secondary objectives are to assess overall survival, and response rate, duration of response, and progression-free survival (PFS) with this regimen using RECIST 1.1 criteria. The exploratory objectives are to assess PFS, overall response rate, duration of response, and disease control rate using the immune-related RECIST (irRECIST) criteria, evaluate the correlation between PD-L1 expression levels and antitumor activity of MK-3475, investigate other biomarkers that may correlate with tumor responses, and evaluate differences in tumor tissue characteristics in biopsies taken during or post-treatment with MK-3475 versus baseline.

Safety, Tolerability, and Efficacy of Doxorubicin and Pembrolizumab for Sarcoma

A Pilot Study Evaluating the Safety, Tolerability, and Efficacy of Doxorubicin and Pembrolizumab in Patients With Metastatic or Unresectable Soft Tissue Sarcoma

Severe or life-threatening adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one adverse event that meets the following criteria: is considered a serious adverse event (per CFR 21 Part 312), is study treatment related per the Sponsor-Investigator, and considered to be clinically significant by the Sponsor-Investigator. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either pembrolizumab, doxorubicin, or both.

OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.

PFS is defined as time from enrollment to time of progression or death. Disease progression (PD) may be determined objectively per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, where PD is defined as a 20% increase in the sum of longest diameters of target lesions, a measurable increase in non-target lesion, or appearance of new lesions) or subjectively as determined by investigator (with evidence documented in the medical records). If the subject died without documented PD, date of progression will be date of death. For surviving subjects who did not have documented PD, PFS was censored at last radiologic assessment. For subjects who received subsequent anticancer therapy prior to documented PD, PFS was censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who experienced a PFS event following an interval equal to two or more scheduled radiologic assessments were censored at last assessment prior to first missed assessment.

Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by \>=30% decrease in sum of longest diameter of target lesions with baseline as reference.

Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.

Merck Sharp & Dohme LLC

Wake Forest University Health Sciences

Participants will receive pembrolizumab IV infusion and doxorubicin IV injection on Day 1 of every 21 (+/- 3) days

Pembrolizumab: IV infusion on day 1 of each 3 week cycle, at dose of 200 mg

Doxorubicin: IV injection on day 1 of each 3 week cycle, starting at dose of 60 mg/m2 (may be escalated to 75 mg/m2 per investigator discretion after Cycle 1)

Pembrolizumab + Doxorubicin

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Primary Tumor Site

Histology

Metastatic Site

Prior Lines of Systemic Treatment for Sarcoma

Chair of Biostatistics Department

The reported severe or life-threatening adverse event rate with weekly doxorubicin and dacarbazine was 0.55. If it became evident that the rate of severe or life-threatening toxicity convincingly exceeded 0.55, the study would have been halted. Convincing evidence of exceeding 0.55 was based on Bayesian methods and continuous monitoring, where the stopping rule would have held enrollment if the posterior probability at any point exceeded 0.75 or higher.

The evaluable population will consist of all subjects who begin study therapy.

Number of Participants With at Least One Severe or Life-Threatening Adverse Event

The evaluable population consisted of all enrolled subjects who began study therapy.

Overall Survival (OS)

Progression-free Survival (PFS)

The evaluable population will consist of all subjects who begin study therapy and have measurable disease at baseline.

Number of Subjects With an Objective Response

The evaluable population consisted of all enrolled subjects who begin study therapy and achieve objective response (CR or PR) on study treatment.

Duration of Response (DoR)

Overall Study

Skin and Connective Tissue Diseases

Osteosarcoma

Sarcoma, Ewing

Chordoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Germ Cell and Embryonal

Ewing Sarcoma

Cohort 1: Patients with Limb/limb girdle soft tissue sarcoma (STS) receiving (neo)-adjuvant radiotherapy (Intensity Modulated Radiotherapy)

Dose schedules for Cohort 1:

* Pre-operative RT - 50 Gy in 25 daily fractions over 5 weeks
* Post-operative RT - 60 Gy in 30 daily fractions to the high dose planning target volume (PTV) and 52.2 Gy in 30 daily fractions to the low dose PTV treated concurrently over 6 weeks
* Post-operative RT (positive resection margins) - 66 Gy in 33 daily fractions to the high dose PTV, and 53.46Gy in 33 fractions to the low dose PTV treated concurrently over 6 ½ weeks.

Cohort 2: Patients with Ewing sarcoma of the spine/pelvis receiving definitive radical or (neo)-adjuvant radiotherapy (Intensity Modulated Radiotherapy)

Dose schedules for Cohort 2:

* Pre-operative RT - 50.4 Gy in 28 daily fractions over 5½ weeks
* Post-operative RT - 54 Gy in 30 daily fractions over 6 weeks
* Primary RT - 54 Gy in 30 daily fractions over 6 weeks.

Cohort 3: Patients with non-Ewing primary bone sarcomas of the spine/pelvis receiving definitive radical or adjuvant Radiotherapy (Intensity Modulated Radiotherapy)

Dose schedule for Cohort 3:

* Primary RT - 70 Gy in 35 daily fractions over 7 week
* Post-operative RT (non-chordoma) - primary bone sarcoma 60 Gy in 30 daily fractions over 6 weeks
* Post-operative RT (chordoma) - 70 Gy in 35 daily fractions over 7 weeks.

Intensity modulated radiotherapy (IMRT) is an advanced radiotherapy technique that is able to deliver a highly conformal dose to a target with improved sparing of the surrounding normal tissues from moderate to high radiation doses. IMRT is likely to be of particular benefit for tumours that have complex shapes, or those in close proximity to sensitive normal tissues and critical organs. Reducing the dose to normal tissues may in turn reduce the acute and late side effects of treatment. IMRT can be delivered from multiple fixed beam angles or through rotational arc applications such as volumetric modulated arc therapy (VMAT) and tomotherapy. The radiotherapy is delivered using multiple small beams (beamlets) of non-uniform intensity.

Intensity modulated radiotherapy (IMRT)

Beatrice Seddon, Ph.D., M.D

IMRiS is a phase II trial which aims to assess the feasibility, efficacy and toxicity of Intensity Modulated Radiotherapy (IMRT) in three different cohorts of patients with primary bone and soft tissue sarcoma and to demonstrate whether IMRT can improve on current clinical outcomes.

Cohort 1 of the trial is now closed to recruitment.

IMRiS is a prospective multicentre phase II trial of Intensity Modulated Radiotherapy (IMRT). The trial is aiming to evaluate the role of intensity modulated radiotherapy (IMRT) in soft tissue and bone sarcomas. Three separate sarcoma cohorts will be studied and will be analysed separately. Patients will be enrolled in one of three cohorts depending on the type of sarcoma they have:

Cohort 1- Patients with Limb/limb girdle soft tissue sarcoma receiving (neo)-adjuvant radiotherapy. (closed to recruitment)

Cohort 2- Patients with Ewing sarcoma of the spine/pelvis receiving definitive radical or (neo)-adjuvant radiotherapy.

Cohort 3- Patients with non-Ewing primary bone sarcomas of the spine/pelvis receiving definitive radical or adjuvant radiotherapy.

Dose schedules for each Cohort have been indicated in the Trial Arm description.

Radiotherapy will be delivered with fixed beam IMRT, arc IMRT techniques, or tomotherapy. All trial patients will be followed up until death or a maximum of three years from the date of registration in the trial.

The theoretical advantage to IMRT is the potential reduction in late toxicity and subsequent potential for functional improvement. There have been no prospective studies to date powered to address this, particularly where IMRT is used post-operatively. IMRiS cohort 1 will address this question and establish if the use of IMRT will reduce late normal tissue toxicity.

In cohorts 2 \& 3, the aim is to establish if the use of IMRT will enable the achievement of a radiotherapy treatment plan that delivers the optimal dose while keeping within normal tissue tolerances. There have been no clinical trials of IMRT in Ewing sarcoma and there is very little published on the use of IMRT in high grade bone sarcomas and chordomas. It is important to establish the feasibility of IMRT to achieve the required radiation doses to the tumour, and to prospectively document the side effects of treatment in this setting. IMRiS will address this in cohort 2 and cohort 3.

A Study of IMRT in Primary Bone and Soft Tissue Sarcoma

A Phase II Study of Intensity Modulated Radiotherapy (IMRT) for Patients With Primary Bone and Soft Tissue Sarcoma

Late toxicity assessment measured using RTOG late radiation morbidity criteria.

Cohorts 2 (Ewing's sarcoma of the spine/pelvis): The proportion of patients in whom 90% of the planPTV receives 95% of the optimal prescription dose.

Cohort 3 (Non-Ewing's primary bone sarcomas of the spine/pelvis): The proportion of patients in whom 80% of the planPTV receives 95% of the optimal prescription dose.

In all 3 cohorts, Acute RT toxicity measured using RTOG acute radiation morbidity criteria.

In all 3 cohorts, late toxicities measured using the RTOG/EORTC Late Radiation Morbidity Scoring Criteria (skin, subcutaneous tissue fibrosis, bone, joint stiffness) and Stern's scale for oedema

All cohorts, patient reported Quality of life measured using EORTC QLQ-C30 quality of life questionnaire

For patients in Cohort 1 only, patient reported limb function measured using TESS questionnaire

Disease free survival will be calculated from the date of registration to date of documented disease progression, or death from any cause. Where progression is suspected and subsequently confirmed by scans, the date of documented suspected progression will be used. Patients alive and disease-free will be censored at the date last seen.

Overall survival time will be calculated from date of registration to the date of death from any cause or end of trial follow up

Time to local tumour recurrence evaluation from date of registration to first diagnosis of recurrence (histological or radiological).

Time to local disease progression evaluation from date of registration to first diagnosis of progression.

Response measured according to RECIST v 1.1 (for definitive radical RT)

Rate and severity of wound complications assessed up to 120 days post surgery. This is a composite outcome measure assessed by a clinical examination of the wound.

Percentage volume of planPTV receiving 95% of the prescription dose (50.4Gy/54Gy for cohort 2 and 60Gy/70Gy for cohort 3)

Dose delivered to 95%, 80%, 70%, 60% and 50% volume of planPTV.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety, Tolerability, and Efficacy of Doxorubicin and Pembrolizumab for Sarcoma	NCT03056001	Soft Tissue Sar... Soft Tissue Sar...	Pembrolizumab Doxorubicin	12 Years -	Wake Forest University Health Sciences
A Study of IMRT in Primary Bone and Soft Tissue Sarcoma	NCT02520128	Soft Tissue Sar... Ewing Sarcoma Bone Sarcoma Chordoma	Intensity modul...	16 Years -	University College, London
Safety, Tolerability, and Efficacy of Doxorubicin and Pembrolizumab for Sarcoma	NCT03056001	Soft Tissue Sar... Soft Tissue Sar...	Pembrolizumab Doxorubicin	12 Years -	Wake Forest University Health Sciences
Safety, Tolerability, and Efficacy of Doxorubicin and Pembrolizumab for Sarcoma	NCT03056001	Soft Tissue Sar... Soft Tissue Sar...	Pembrolizumab Doxorubicin	12 Years -	Wake Forest University Health Sciences

Spots Global Cancer Trial Database for soft tissue sarcoma, adult