Neoplasms

All Conditions

Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Trabectedin

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen will receive drug treatment with trabectedin (1 cycle mono-therapy) followed by trabectedin/nivolumab combination (up to 15 additional cycles); 16 cycles in total

Patients with unresectable or metastatic soft tissue sarcoma other than liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen (GIST excluded) will receive drug treatment with trabectedin (1 cycle mono-therapy) followed by trabectedin/nivolumab combination (up to 15 additional cycles); 16 cycles in total

Cycle 1 to 16 1.5mg/m² IV over 24 hours, q3w

Cycle 2 to 16 240 mg IV over 30 minutes, q3w

Daniel Pink, MD

The "NiTraSarc" trial evaluates the efficacy and feasibility (as determined by the safety and tolerability) of combined treatment with trabectedin and nivolumab in patients with metastatic or inoperable soft tissue sarcomas

Undoubtedly, there is a strong medical need for new efficacious therapies for patients with advanced soft tissue sarcomas. While immune oncology treatment approaches like inhibition of immune checkpoints by administration of anti PD-1 / PD-L1 antibodies displayed very promising clinical activity in several types of tumors, current data points out to only limited activity of mono-agent immunotherapy in soft tissue sarcomas (especially in leiomyosarcomas) - although this type of tumor demonstrably displays a certain grade of immunogenicity. That means, STS patients are currently not able to benefit from the advancements in cancer immunotherapy which led to remarkable improvements in outcome in some other tumor entities in the last few years.

Interestingly, most recent data indicates that trabectedin could enhance the activity of immune-modulating agents via its influence on the tumor micro-environment and the reduction of tumor associated macrophages. Furthermore, first clinical data obtained from a feasibility study on combined nivolumab/trabectedin therapy in STS patients did not report on significant toxicities when combining the two agents, thereby justifying combination of nivolumab and trabectedin utilizing standard dosages.

Therefore, this phase II study will examine if combination of nivolumab with trabectedin is feasible (safe and well tolerated) and efficacious by utilizing potential synergistic effects of both agents. In the long run, the results of this phase II trial could build the basis for further evaluation of the efficacy of the trabectedin / nivolumab combination in a randomized clinical trial involving larger patient numbers. Finally, this could render patients with STS accessible to immunotherapeutics - a promising new class of drugs for anti-cancer treatment.

Combined Treatment With Nivolumab and Trabectedin in Patients With Metastatic or Inoperable Soft Tissue Sarcomas

NiTraSarc Combined Treatment With Nivolumab and Trabectedin in Patients With Metastatic or Inoperable Soft Tissue Sarcomas - The NiTraSarc Phase II Trial

The primary efficacy endpoint of the trial is the progression-free survival rate after 6 months (PFSR6), assessed by applying RECIST 1.1.

The primary safety endpoint is to assess the feasibility of combined treatment with trabectedin and nivolumab in patients with metastatic or inoperable soft tissue sarcomas as determined by the safety and tolerability of the combination treatment.

Objective Response Rate (ORR) defined as the number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression per RECIST v1.1 or the date of subsequent therapy or death date, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.

OS is defined as the time from date of the first dosing date of any study medication to the date of death (due to any cause). Subjects who are alive will be censored at the last known alive dates.

PFS is defined as the time from the first dosing date of any study medication to the date of the first objectively documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause. Subjects who die without a reported prior progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on the first dosing date of study medication. Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. In addition to PFS according to RECIST v1.1, PFS according to immune related RECIST 1.1 (irRECIST 1.1) will be determined.

Duration of disease stabilization is defined as the sum of duration of response (DoR) and duration of stable disease (DoS) in months. So DoDS is applicable to subjects with best overall response as either CR or PR or SD and it is defined as time from the first assessment of CR or PR or SD until the date of the first occurrence of PD, or until the date of death (if occurred within predefined time period). In case of censored event, the DoDS is censored on the date of last tumor assessment.

PDL-1 expression will be quantified during central pathological examination

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

PharmaMar

Bristol-Myers Squibb

University Medicine Greifswald

Digestive System Diseases

Substance Related Disorders

Skin and Connective Tissue Diseases

Gastrointestinal Stromal Tumors

Drug-Related Side Effects and Adverse Reactions

Neoplasms, Connective Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Chemically-Induced Disorders

Amino Acids

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

This is a single-arm, two-cohort, open label phase Ib/II trial studying the combination of oral imatinib 400 mg, once daily, and oral selinexor given once weekly (Cohort A); and single-agent oral selinexor 60 mg BIW (Cohort B). The study will consist of:

* Cohort A: an initial escalation phase (Ib) evaluating increasing doses of selinexor in combination with fixed doses of imatinib administered in repeated 28-day cycles in advanced/metastatic, imatinib-resistant GIST patients, followed by en expansion phase (II) testing for safety and preliminary evidence of antitumor activity
* Cohort B: single-agent, fixed selinexor dose in the same target population

oral selinexor given once weekly (Cohort A), oral selinexor given BIW (Cohort B)

Selinexor

Imatinib

Cesar Serrano, MD

This is a single-arm, two cohort, open label phase I/II clinical trial studying the combination of oral imatinib 400 mg, once daily, and oral selinexor given once weekly (Cohort A); and single-agent oral selinexor 60 mg BIW (Cohort B). The study will consist of:

* Cohort A: an initial escalation phase (Ib) evaluating increasing doses of selinexor in combination with fixed doses of imatinib administered in repeated 28-day cycles in advanced/metastatic, imatinib-resistant GIST patients, followed by an expansion phase (II) testing for safety and preliminary evidence of antitumor activity
* Cohort B: single-agent, fixed selinexor dose in the same target population

Clinical Study Objectives:

Primary clinical study objective

Cohort A:

1.- To determine the maximum tolerated dose (MTD) and recommended phase II doses (RP2D) of selinexor in combination with imatinib among unresectable and/or metastatic GIST patients with prior failure to at least imatinib for advanced/metastatic disease.

Cohort B:

1. To evaluate the clinical benefit rate (CBR: CR+PR+SD ≥ 16 wks)

Secondary clinical study objectives (both cohorts A and B)

1. To evaluate the clinical benefit rate (CBR: CR+PR+ SD ≥ 16 wks)
2. To evaluate progression free survival (PFS)
3. To evaluate overall survival (OS)
4. To evaluate the objective response rate (ORR)
5. To evaluate the safety profile according to CTCAE 4.03
6. To compare PFS on selinexor and imatinib and on selinexor in monotherapy with PFS on last prior anti-cancer therapy.

Translational Study Objective - To explore the relationship between GIST genotype and CBR with selinexor and imatinib, and selinexor as single-agent

Pharmacokinetics Study Objective

- To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.

Phase Ib/II, single-arm, two-cohort, non-randomized, open-label, multicenter, national clinical trial, single agent, combinations products

Selinexor as Single Agent and With Imatinib in Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (SeliGIST)

A Multicenter, Phase Ib/II Trial of Selinexor as a Single Agent and in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GISTs)

The final publication of the trial results will be written by the international coordinating investigators on the basis of the final analysis performed. The draft manuscript will be reviewed by the coordinating investigators and other co-authors. After revision the manuscript will be sent to a major scientific journal. Results obtained in the different strata may be separately published.

Maximum tolerated dose (MTD) is defined as the highest dose level with ≤1 out of 6 patients experiencing a dose limiting toxicity (DLT) during the first 28 days of treatment. Dose escalation cohort (Phase 1b) seeks to determine the frequency and characteristics of DLTs of the selinexor plus imatinib combination at each dose level during the first cycle of therapy. Phase Ib will be carried out in standard 3+3 format, based on the toxicities found during the first cycle of therapy.

Clinical benefit rate (CBR) is defined as CR+PR+SD ≥ 16 wks

Efficacy measured by PFS assessed by median time. PFS is defined as the time between the date of first experimental treatment dose and the date of disease progression (according to RECIST 1.1 criteria).

Efficacy measured by OS. OS is defined as the time between the date of first experimental treatment dose and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive, or when the last enrolled patiens are followed up to for 12 months, whichever is early.

Efficacy measured by ORR. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 and Choi criteria).

Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.

Toxicity will be graded and tabulated by using CTCAE 4.03.

GIST genotype determinations and its correlation with response to the treatment with selinexor and imatinib in terms of clinical benefit (CBR).

To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.

Number of patient with CBR ≥ 30% lasting ≥ 16 weeks

Grupo Espanol de Investigacion en Sarcomas

Symptoms and General Pathology

Recurrence

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Durvalumab

Tremelimumab

Anti-Bacterial Agents

Antibiotics, Antitubercular

Cycles/courses 1-3:

Durvalumab 1.5g q4wks Tremelimumab 75 mg q4wks

Cycles/courses ≥4:

Durvalumab 1.5g q4wks Tremelimumab 75 mg q12wks

Durvalumab and Tremelimumab

Viktor Grünwald, Dr.

The objective of the trial is to assess the efficacy of Durvalumab and Tremelimumab in comparison to doxorubicin in treatment-naïve Soft tissue sarcoma patients

Treatment Arm A: Combination of Durvalumab and Tremelimumab Treatment Arm B: Doxorubicin

Durvalumab and Tremelimumab Compared to Doxorubicin in Patients With Advanced or Metastatic Soft Tissue Sarcoma

A Randomized Phase II Study of Durvalumab (MEDI4736) and Tremelimumab Compared to Doxorubicin in Patients With Advanced or Metastatic Soft Tissue Sarcoma

Assessment of adverse events of tremelimumab and durvalumab (MEDI4736) combination therapy

scores according to EORTC QLQ-C30 scoring manual (Quality of life)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combined Treatment With Nivolumab and Trabectedin in Patients With Metastatic or Inoperable Soft Tissue Sarcomas	NCT03590210	Metastatic Adul...	Trabectedin Nivolumab	18 Years -	University Medicine Greifswald
Selinexor as Single Agent and With Imatinib in Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (SeliGIST)	NCT04138381	Maximum Tolerat... GIST Metastatic Adul... Drug Toxicity Drug Use	Selinexor Imatinib	18 Years -	Grupo Espanol de Investigacion en Sarcomas
Durvalumab and Tremelimumab Compared to Doxorubicin in Patients With Advanced or Metastatic Soft Tissue Sarcoma	NCT03317457	Metastatic Adul... Recurrent Adult...	Durvalumab and ... Doxorubicin	18 Years -	AIO-Studien-gGmbH

Spots Global Cancer Trial Database for metastatic adult soft tissue sarcoma