Rare Diseases

All Conditions

Lethal Congenital Contracture Syndrome 2

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Mitogens

IV Infusion Dose Escalation (Part 1) - 5 Dose Cohorts Dose Expansion (Part 2) - 30 patients

U3-1287 (AMG888)

This is a Phase 1 clinical study to investigate the safety, pharmacokinetics, and pharmacodynamics of U3-1287 (AMG 888), a fully human monoclonal antibody targeting the HER3 receptor, in patients with advanced solid tumors. Eligible patients will have disease that is refractory or resistant to standard treatments or for which no standard therapy exists. The study will be conducted in two parts; a dose escalation (Part 1) and a dose expansion (Part 2). The hypothesis for this study is that U3-1287 (AMG888) will be safe and well tolerated in patients with advanced solid tumors and will show initial evidence of anti-tumor activity.

Phase I Study of U3P1287/01, Including Patients With Advanced Solid Tumors

A Phase I, Open-label, Dose-Finding Study to Assess the Safety and Tolerability of U3-1287 (AMG 888), a Human Monoclonal Antibody Targeting HER3 in Patients With Advanced Solid Tumors.

U3 Pharma GmbH

Dr Alan Boyd MD

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunomodulating Agents

CAR-T cells to treat advanced lung cancer. This study has only one arm. All participators will attend the screening and meet the set criteria for the clinical treatment. PD-L1 CAR-T cells are infused on day 0 with 10%, day 3 with 30% and day 7 with 60% , (1-2)×10\^6/kg PD-L1 CAR-T cells total.

Drug: fludarabine. On days -4 through -2, fludarabine (25mg/m2) will be infused for 3 consecutive days; Drug: cyclophosphamide. On days -4 through -2, cyclophosphamide (250mg/m2) will be infused for 3 consecutive days.

Patients will receive the above chemotherapy for lymphocyte-depletion followed by PD-L1 CAR-T cells.

CAR-T cells to treat advanced lung cancer

Li Zhang, M.D.

The NSCLC patients who failed the standard treatments, with positive Programmed Death-Ligand 1 (PD-L1) expression, were enrolled into this trial. About 22 advanced NSCLC patients will be screened according to the criteria. The qualified patients will be recruited and sign the informed consent.Participants will be hospitalized and undergo clinical examinations.

Appropriate volume of peripheral blood will be draw (from 66 ml to 360 ml, depend on the body weight and blood routine test), using Ficoll method to centrifuge peripheral blood cell and collected T cells. PD-L1 CAR gene is cloned in a lenti-viral vector that was composed of T cell activation molecules (Cluster of Differentiation 137 (CD137/CD28) and Cluster of Differentiation 3(CD3) zeta intracellular domains) and PD-L1 single-chain variable fragment(scFv) derived from the variable regions of a PD-L1 monoclonal antibody.Then, investigators packaged pseudo-lentiviral particles in human embryonic kidney (293T) cells that will be used to transduce autologous T cells isolated from the patients. CAR positive T lymphocytes will be determined by FACS with florescence labeled goat anti-human F(ab')2. The plasmids, pseudo-lentiviral particles and transduced T cells will be subject to the stipulated tests by a third party.

Patients will receive leukodepletion chemotherapy (cyclophosphamide: 250mg/m\^2 × 3 days; fludarabine: 25mg/m\^2× 3 days). One day later, the chemotherapeutic effects would be assessed. PD-L1 CAR-T cells will be infused on day 0 with 10%, day 3 with 30% and day 7 with 60% (total number is (1-2)×10\^6/kg). The patients will be observed closely for any adverse reactions and if happened, given supportive treatments.

The patients will be discharged on day 14 and will be followed up for two years according to the study scheme, i.e. once a month for the first three months; once every two months in the first year; since then, once a quarter in the second year. The persistence of PD-L1 CAR-T cells in the circulation will be monitored by fluorescent activated cell sorting (FACS) and polymerase chain reaction (PCR). If the patients undergo core needle biopsy, the infiltration of CAR positive cells in the tumor tissue will be evaluated by immunohistochemistry (IHC). The safety profile and anti-tumor efficacy of the CAR-T cells immunotherapy will be assessed during the whole process based on CTCAE v4.1 and RECIST v1.1.

The morbidity and mortality of lung cancer ranks the first in all malignancies. Although targeted therapy such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and activated lymphocyte kinase (ALK)-TKI can prolong non-small cell lung cancer (NSCLC) patients' survival, drug resistance almost occurs inevitably.

In recent years, PD-L1/PD-1 antibodies like Nivolumab and Pembrolizumab, show satisfactory therapeutic potential in the treatment of cancers like melanoma and lung cancer. Latest clinical investigations show that anti-PD-1 or PD-L1 antibody therapy can prolong patients' survival but actually only 20% of patients benefited from it.

Chimeric antigen receptor T-Cell (CAR-T) was genetically modified T lymphocytes by pseudo-lentiviral transduction to provide them with high binding affinity and specificity to the tumor antigen. That affinity was provided by CAR, independent from major histocompatibility complex (MHC).

CAR-T cell immunotherapy had shown tremendous success in the treatment of acute lymphocytic leukemia (ALL). Cluster of Differentiation (CD)-19 CAR-T cell treatment archived as high as 92% complete response rate for refractory and recurrent ALL. When the CAR-T cells targeting Her2/neu were given to the patients, mortality was observed from cardiopulmonary failure due to the weak expression of Her2/neu on the pulmonary epithelial cells. In contrast, Her2/neu antibody (trastuzumab) is widely applied safely in clinic to treat breast cancer patients. It strongly suggests that the CAR-T cells are more potent.

Thus investigators hypothesized that the CAR targeting tumor cell PD-L1 would significantly improve the efficacy of CAR-T cells and extend their application in the treatment of solid tumors, especially lung cancer. Investigators designed and cloned a PD-L1 CAR gene that targets the PD-L1 expressed on tumor cells. Given that PD-L1 CAR-T cells can effectively kill not only PD-L1 positive tumor cells in vivo but also immunosuppressive cells (like myeloid-derived suppressor cells (MDSCs)) inside tumors, they can remarkably improve immunosuppressive tumor microenvironment. Accordingly they can restore the function of tumor infiltrated T-lymphocytes(TILs) to achieve the synergistic effect of killing tumor cells that can greatly enhance the killing effects of PD-L1 CAR-T cells on tumor cells, even eliminate tumors.

The preclinical studies showed that PD-L1 CAR-T cells could be activated by and had significant killing effects on PD-L1 positive tumor cells in vitro. They inhibited tumor growth, while no obvious toxicity have been observed in mouse xenograft models. Investigators decide to explore the safety and efficacy of the new CAR-T cells in the phase I clinical study in the treatment of advanced NSCLC patients.

CAR-T Cell Immunotherapy for Advanced Lung Cancer

Safety and Toxicity of CAR-T Cell Immunotherapy in Patients With Advanced Lung Cancer After Standard Treatment Failure: A Single-Arm and Single-Center Phase I Clinical Study

Using flow cytometry to count of PD-L1 CAR-T cells, calculated the CAR-T cells existence by time after the infusion.

Exploring the correlation of the immune functions of pre- and post-CAR-T cell treatments with the treatment safety and efficacy.

Assessed by the treatment-emergent adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram. Treatment-emergent adverse events will be assessed and recorded according to CTCae v4.02.

No statistical analysis was performed becuase the study was terminated after only 1 patient received treatment.

Tumor response will be assessed according to RECIST V1.1. The overall response rate calculated by the numbers of PR or CR / all patients received treatment. The disease control rate calculated by the numbers of CR PR and stable disease / all patients received treatment.

Guangzhou Yiyang Biological Technology Co., Ltd.

Sun Yat-sen University

Professor

Serious Cytokine Release Syndrome causes interstitial pneumonia disease. CTCAE grade 4, possibly drug related.

Febrile without any courses and respiratory distress that deteriorated quickly into failure in 3 days.He was immediately transferred to the ICU where he received oxygen via nasal cannula and given intravenous infusions of tocilizumab and large doses of methylprednisolone. His symptoms were quickly improved and the pulmonary inflammation became dissipated gradually.

CAR-T cells to treat advanced lung cancer. This study has only one arm. All participators will attend the screening and meet the set criteria for the clinical treatment. PD-L1 CAR-T cells are infused on day 0 with 10%, day 3 with 30% and day 7 with 60% , (1-2)×10\^6/kg PD-L1 CAR-T cells total.

CAR-T cells to treat advanced lung cancer: Drug: fludarabine. On days -4 through -2, fludarabine (25mg/m2) will be infused for 3 consecutive days; Drug: cyclophosphamide. On days -4 through -2, cyclophosphamide (250mg/m2) will be infused for 3 consecutive days.

Patients will receive the above chemotherapy for lymphocyte-depletion followed by PD-L1 CAR-T cells.

Treatment Arm

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

China

Region of Enrollment

Patients tumor staged as IVa with malignant pleural effusion by AJCC Cancer Staging Manual, Eighth Edition (2017).

Tumor Stage

Epidermal growth factor receptor mutation status: wild type

EGFR mutation status

Dr.Yuxiang Ma

Number of Participants With Treatment-Emergent Adverse Events Associated With PD-L1 CAR-T Cell Treatment

Number of Participants Experiencing a Complete (CR) or Partial (PR) Tumor Response

Only 1 patients received treatment and accepted the surveillance of PD-L1 CAR-T cells, and only one detection was performed at Day 7 time point

Numbers of Patients Received Surveillance of PD-L1 CAR-T Cells in Vivo

Assessment of Count of the Functional B Cells in Peripheral Blood.

Assessment of Count of the Functional T Cells in Peripheral Blood.

Overall Study

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Wounds and Injuries

Dermatitis

Vulvar Neoplasms

Radiodermatitis

Skin Diseases

Radiation Injuries

Vulvar Cancer

A sterile gauze was soaked with BH4 solvent (50 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (100 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (200 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (400 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (600 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (800 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (1000 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

Tetrahydrobiopterin

This study was a single-center prospective phase I clinical study to evaluate the effectiveness and safety of BH4 in the treatment of radiation-induced skin injury during vulvar cancer radiotherapy.

Vulvar Cancer is a type of rare gynecological malignant tumor, accounting to2\~5% of all the female reproductive system malignancies, and mostly occurs in the postmenopausal women. The incidence of vulva cancer is on the rise, especially in the elderly women, with age 75 years and above. It may be related to non-neoplastic epithelial lesions such as lichen sclerosus of the vulva and atypical hyperplasia of the epithelial cells caused by advanced age.

Radiotherapy plays a key role in the treatment of vulvar cancer. High risk factors for postoperative recurrence include positive surgical margin, adjacent surgical margin (\<8 mm), lymphovascular space invasion (LVSI), lymph node metastasis (especially more than two metastatic nodes), and extracapsular invasion of lymph nodes. Patients with high risk factors for postoperative recurrence can benefit from radiotherapy. Radical radiotherapy and chemotherapy could be provided to patients with unresectable locally advanced tumors, including part of stage II (tumor diameter\> 4 cm or tumor invading vagina, urethra, and anus), and to early-stage patients with possible serious postoperative complications or serious complications that do not allow surgery as an option. Due to the dampness of the vulva and the poor tolerance of the skin and mucous membranes to radiation, most patients with vulvar cancer have severe skin damage during radiotherapy, significantly affecting their treatment process, worsening their prognosis, and impairing their quality of life. Seeking safe and effective prevention and treatment measures for radiation-induced skin injury is particularly important to improve the prognosis of patients and improve their quality of life.

Free radicals generated by the indirect action of ionizing radiation on skin cells are considered to be the primary cause of radiation skin injury. Tetrahydrobiopterin (BH4), also known as Sapropterin, is an important cofactor of the nitric oxide synthase (NOS) enzyme. Under normal physiological conditions, guanosine triphosphate cyclohydrolase 1 (GCH1) is the key enzyme for the synthesis of BH4. Reduced GCH1 activity lowers the production of BH4, causing NOS uncoupling, thereby leading to a raised level of oxygen free radicals (reactive oxygen species, ROS). Studies have shown that GCH1 overexpression restores the BH4 level and NO products in irradiated skin cells, reversed and inhibited the NOS uncoupling caused by ionizing radiation, thereby eliminating the ROS induced by ionizing radiation, reducing DNA damage, and postponing the cell apoptosis and cell aging. In animal experiments, direct injection of BH4 under the skin did not only reduce the degree of acute radiation skin injury, but also promoted the repair of the skin damage, lowered the occurrence of radiation-induced skin fibrosis, and maintained the normal physiological functions of the skin.

This study was a single-center prospective phase I clinical study. The phase I clinical trial included 21 patients. Given satisfactory results, the cases appropriate for the study of drug concentration were expanded to 25, with a total of 45 subjects included eventually. The subjects of the study were pathologically diagnosed vulvar cancer patients, who needed postoperative supplemental radiotherapy, patients who received radical radiotherapy and chemotherapy (unresectable locally advanced tumors, including some stage II with tumor diameter \> 4 cm or tumor invading vagina, urethra, and anus), and early-stage patients with possible serious postoperative complications or serious complications, wherein the option of undergoing a surgery was not appropriate.

Intensity-modulated radiation therapy (IMRT) was employed, using the conventional split mode, (1.8\~2.0) Gy/day, 5 times/week. The vulva and pelvic clinical target volume (CTV) was (45\~50) Gy/25 times. The boost applied for primary visible lesions and metastaticlocal lymph nodes was (60\~70) Gy. The techniques for boost regarding residual tumor and tumor bed area were determined based on the tumor location and the radiation dose limit of the surrounding organs. The electron beam vertical irradiation was applied for tumors located superficially. For residual tumors good for brachytherapy, techniques such as near-distance post-implantation were adopted to give a radiation boost. The specific dose and type of the radiation was determined according to the tumor location, size, treatment response, acute side effects, and whether chemotherapy was accompanied or not. For late-stage, metastatic vulvar cancer patients and those received radical chemotherapy and radiotherapy, systemic chemotherapy was provided, with unrestricted chemotherapy regimens.

The degree of the skin injury during the radiotherapy was assessed according to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG). After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.

The degree of the skin injury during the radiotherapy was assessedaccording to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG).After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.

A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury

Clinical Professor

Follow-up until the death of the patient or withdraw from the clinical study

incidence that was evaluated every week (according to RTOG radiation morbidity scoring criteria)

It was evaluated one month and three months after the end of treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Study of U3P1287/01, Including Patients With Advanced Solid Tumors	NCT00730470	Advanced Solid ...	U3-1287 (AMG888...	18 Years -	U3 Pharma GmbH
CAR-T Cell Immunotherapy for Advanced Lung Cancer	NCT03330834	Advanced Lung C...	CAR-T cells to ...	18 Years - 65 Years	Sun Yat-sen University
A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury	NCT05114226	Radiation-Induc...	Tetrahydrobiopt...	18 Years -	West China Second University Hospital
CAR-T Cell Immunotherapy for Advanced Lung Cancer	NCT03330834	Advanced Lung C...	CAR-T cells to ...	18 Years - 65 Years	Sun Yat-sen University
Phase I Study of U3P1287/01, Including Patients With Advanced Solid Tumors	NCT00730470	Advanced Solid ...	U3-1287 (AMG888...	18 Years -	U3 Pharma GmbH

Spots Global Cancer Trial Database for phase i clinical study