Detailed Description:. MedlinePlus related topics: Breast Cancer Hormones. Drug Information available for: Fulvestrant. FDA Resources. Arms and Interventions. Other Name: palbociclib,Ibrance,ribociclib,Kisqali,abemaciclib,Verzenio. Outcome Measures. Primary Outcome Measures : PFS2 [ Time Frame: Until objective disease progression, symptomatic deterioration, or unacceptable toxicity on second line treatment, death, strategy violation, or withdrawal of consent, whichever occurs first, assessed up to 60 months ] Progression-free survival after two lines of treatment PFS2.
Safety assessment will consist of monitoring of all grade 3 and grade 4 elevated liver enzymes elevation compared to upper limit of normal. Safety assessment will consist of monitoring of all grade 3 and grade 4 other toxicities as defined in CTCAE v4. The cost and outcomes of both arms will be assessed by means of a decision model a multistate Markov model or a Discrete Event Simulation model.
Circulating tumor DNA isolated from blood samples collected at 7 timepoints during the study. Tissue microarray on archived FFPE tissue blocks of the tumor. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Evidence of a personally signed and dated informed consent document indicating that the patient or a legal representative has been informed of all pertinent aspects of the study before any study-specific activity is performed. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy e.
Patients treated within the last 7 days prior to randomization with: Food or drugs that are known to be CYP3A4 inhibitors ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice ; Drugs that are known to be CYP3A4 inducers ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St.
John's wort. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomization. Diagnosis of any other malignancy prior to randomization, except those that are not believed to influence the patient's prognosis and do not require any further treatment.
This includes, but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix. Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to any palbociclib excipients. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Recent or active suicidal ideation or behavior. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. Layout table for location contacts Contact: A. Primary Outcome Measures : Effect of trilaciclib on Overall Survival OS compared with placebo [ Time Frame: From the date of randomization to the date of death for patients who died in the study due to any cause, or to the last contact date known to be alive for those who survived as of the data cutoff date, assessed up to 30 months.
To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on objective response rate ORR and duration of objective response DOR in patients with metastatic NSCLC receiving docetaxel in the second or third line.
To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on duration of severe grade 4 neutropenia in cycle 1, occurrence of severe grade 4 neutropenia, occurrence of febrile neutropenia AEs, and occurrence of granulocyte colony-stimulating factor G-CSF administration in patients with metastatic NSCLC receiving docetaxel in the second or third line.
To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on occurrence of grade 3 or 4 decreased hemoglobin laboratory values, red blood cell RBC transfusions on or after week 5 occurrence and number of transfusions , occurrence of erythropoiesis stimulating agent ESA administration in patients with metastatic NSCLC receiving docetaxel in the second or third line.
To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on occurrence of grade 3 or 4 decreased platelet count laboratory values and platelet transfusions occurrence and number of transfusions in patients with metastatic NSCLC receiving docetaxel in the second or third line. To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on all-cause dose reductions occurrence and number of reductions and all-cause cycle delays occurrence and number of delays in patients with metastatic NSCLC receiving docetaxel in the second or third line.
To assess the effects of trilaciclib administered prior to docetaxel compared with placebo administered prior to docetaxel on occurrence and number of hospitalizations due to chemotherapy induced myelosuppression in patients with metastatic NSCLC receiving docetaxel in the second or third line.
Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Patients must have had documented disease progression during or after 1 or 2 lines of systemic treatment for recurrent or metastatic disease. Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate line of therapy.
Maintenance therapy is defined as therapy given within 42 days after the last dose of platinum-based chemotherapy in patients with ongoing clinical benefit complete response [CR], partial response [PR] or stable disease [SD]. A formalin-fixed paraffin-embedded FFPE tumor specimen from archival or fresh biopsy with an associated pathology report documenting NSCLC must be available to send to the Sponsor, within the specified timeframe, for planned retrospective biomarker analyses.
Adequate organ function defined by the normal laboratory values. Exclusion Criteria: Prior therapy with docetaxel. Any contraindication to the administration of docetaxel at the discretion of the investigator. Presence of central nervous system CNS metastases requiring immediate treatment with radiation therapy or steroids i. Presence of leptomeningeal disease.
Significant third-space fluid retention ex. Dinaciclib mainly inhibits the activity of CDK9, thus preventing the phosphorylation of the carboxyl terminus of RNA polymerase II, which plays a transcriptional inhibitory role and induces cell apoptosis. Strikingly, it has been proved that Dinaciclib has the best therapeutic efficacy for leukemia.
In acute lymphoblastic leukemia, Dinaciclib inhibited the growth of T-ALL cells and prolonged the survival time of mouse tumor xenograft models. The number of leukocytes was significantly reduced in the mouse tumor model, showing a stronger survival advantage, with median survival increased from 33 days to 52 days [ 24 ]. These studies indicated that Dinaciclib has great potential as a clinical treatment agent for CLL.
Clinical trial results also showed that Dinaciclib was superior to Flavopiridol in the treatment of CLL. Recent studies have further demonstrated that Dinaciclib has a more remarkable anti-tumor effect when combined with PD1 monoclonal antibodies [ 26 ], making Dinaciclib a potential promising therapeutic target in clinical setting. P showed significant cytotoxicity against mantle cell lymphoma MCL cells in vitro [ 27 ]. Overall, both drug resistance and anti-tumor effects were significant.
At present, the molecular mechanism of p in the treatment of MCL remains unclear [ 28 ]. Other studies have shown that p can arrest the cell cycle in the G1 phase, thereby inducing apoptosis of head and neck cancer cells [ 29 ].
The anti-tumor activity and safety of p was evaluated in a phase II clinical study in patients with recurrent and locally advanced head and neck cancer. The results suggested that P had good anti-tumor activity, while its safety needs to be further evaluated. Preclinical studies have shown that TG02 alone or in combination with TMZ can inhibit the proliferation of glioblastoma cells [ 30 ].
Phase I clinical studies have been conducted in China to determine the clinical dose and efficacy of TG The results showed that TG02 is effective in the treatment of hematological malignancies, and TG02 therapy has been found to promote tumor deposition and prolong survival in a variety of mouse models of leukemia. In conclusion, TG02 has shown promising therapeutic potentials in clinical trials, although further investigation is still needed in the future.
Studies have shown that AT not only has inhibitory activity against a variety of solid tumors, but also can inhibit hematologic malignancies.
Preclinical trials have proved that AT can induce apoptosis in various neuroblastoma cell lines [ 33 ]. In addition, AT also induces neutrophils apoptosis and reduces inflammatory response in a pneumonia model. So, AT has been evaluated as a potential agent for ARDS acute respiratory distress syndrome with neutrophil dominant in many studies [ 34 ].
Phase I clinical trials also provided guidance for dosages of AT to be used in Phase II clinical trials, with a recommended dose of AT is in phase II clinical trials for the treatment of relapsed mantle cell lymphoma and recurrent refractory chronic lymphocytic leukemia. Furthermore, AT in combination with Onalespib HSP90 inhibitor for the treatment of metastatic or unresectable solid tumors and AT in combination with Bortezomib for the treatment of multiple myeloma are also in clinical trials [ 35 ].
Together, AT exhibited great potential for clinical application. Roniciclib is an oral pan-CDK inhibitor.
A study at the National University of Singapore Cancer Institute indicated that Roniciclib combined with cisplatin has a significant synergistic anti-tumor effect [ 36 ].
Another preclinical study showed that Roniciclib induced apoptosis of medullary thyroid cancer cells. The combination of Roniciclib and Soafenib further inhibited tumor growth in xenograft models compared to Roniciclib alone [ 37 ]. To date, the safety and tolerated dose of Roniciclib in patients with advanced malignancy have been evaluated in phase I clinical trials, and Roniciclib in combination with conventional chemotherapy agents for the treatment of extensive non-small cell lung cancer ED-SCLC has entered phase II clinical trials [ 38 ].
Unfortunately, the results showed that the combination treatment produced significant side effects and cytotoxicity, so the phase II clinical trial was terminated [ 39 ]. Therefore, the future development of Roniciclib might need to be re-optimized in terms of the dosage and administration strategy. Preclinical experiments have shown that RGB can induce apoptosis of various human cancer cell lines.
Intravenous injection of RGB for 5 consecutive days had the best inhibition effect on tumor growth in solid tumor and hematoma mouse models. Based on experience in preclinical trials, a phase I clinical trial of RGB is currently being conducted to evaluate safety and drug resistance in patients with recurrent or refractory blood cancer [ 41 ].
The clinical application of RGB still needs further investigation. The low concentration of PHA inhibits the phosphorylation of Rb protein, and thus prevents the progression of cell cycle [ 42 ].
In vitro experiments showed that PHA had a certain toxic effect on leukemia cells. Subcutaneous xenograft model and primary leukemia cell dissemination model were used to evaluate the therapeutic effect of PHA in vivo, and the results sound promising [ 43 ]. However, in a phase I clinical trial, there were 19 patients who showed severe hepatotoxicity.
Therefore, the clinical application of PHA is still under development [ 44 ]. The biggest challenge in the clinical application of pan-CDK inhibitors is their low specificity and significant side effects on normal somatic cells.
Each type of tumor is associated with its own CDK expression landscape, selection of appropriate specific CDK inhibitors for relevant patients is therefore expected to assure the therapeutic effect, and to avoid toxic and side effects as well. At present, a variety of specific CDK inhibitors have shown significant anti-tumor effects in preclinical and clinical studies.
Here, we briefly summarized the characteristics of some specific CDK inhibitors and their anti-tumor activity. Ribociclib is very similar to Palbociclib in structure, but Abemaciclib is quite different. CDK7 has dual functions of cell cycle controlling and transcriptional regulation, which make CDK7 a potential target for cancer therapy.
BS is the first highly selective CDK7 inhibitor. Preclinical studies have shown that BS inhibits cancer cell proliferation and xenograft tumor growth, but its bioavailability is poor and cell permeability is insufficient [ 49 ].
Preclinical studies have shown that THZ1 has strong anti-tumor activity in several cancer types [ 52 - 57 ]. Preclinical studies have shown that YKL can potentiate genomic instability and trigger anti-tumor immune response in small cell lung cancer, which provides a theoretical basis for the combination therapy of CDK7 inhibitors and immunotherapy [ 59 ].
SY, a THZ1 derived CDK7 inhibitor, entered phase I clinical trial in advanced solid tumors in May to evaluate its efficacy in the treatment of ovarian and breast cancer [ 60 ] ClinicalTrials. SY is another selective CDK7 inhibitor. CDK9 regulates cellular transcriptional elongation and mRNA maturation, and has become an attractive therapeutic target for many cancers, especially those caused by dysregulation of transcription [ 63 , 64 ].
In addition, Fadraciclib combined with temozolomide can effectively suppress MYCN-amplified neuroblastoma long-term [ 65 ]. Preclinical studies have demonstrated that AZD has significant anti-cancer efficacy in hematologic malignancies [ 66 , 67 ]. The results of these preclinical studies have promoted the development of CDK9 inhibitors for clinical application. A recent review summarized the progress of sixteen CDK9 inhibitors in various stages of clinical development for cancer therapy.
Thus, they are also considered as pan-CDK inhibitors. Due to the high homology of these CDKs in the catalytic domain, the development of specific CDK9 inhibitors remains a major challenge. Several novel functions of CDK12 in cancer, especially breast cancer, have been revealed in recent studies. In recent years, several CDK12 inhibitors have been developed. These inhibitors include SR and THZ, which presented strong anti-tumor activity in preclinical studies.
Recent studies indicated that THZ has a striking synergistic effect with sorafenib in the treatment of hepatocellular carcinoma [ 84 ]. Therefore, development of CDK12 inhibitors with high specificity and drug properties is needed. Through decades of research, cancer immunotherapy has emerged as a powerful and effective strategy for cancer treatment. In , Dr. Thus, blocking PD1-PDL1 immune checkpoints promotes T cell activation, which facilitates the cytotoxic effect of T cells on tumor cells.
Although the blockade of the immune checkpoint PD1-PDL1 has achieved remarkable success in the clinical treatment of a variety of cancers, the majority of cancer patients still failed to respond to the immunotherapy. Therefore, many trials have been conducted to improve the responsiveness of cancer patients to immunotherapy through combination therapy strategies. Recent studies have shown that some CDK inhibitors can enhance the anti-tumor immune response.
In preclinical and clinical trials, some CDK inhibitors have demonstrated potent anti-tumor activity when used in combination with PD1-PDL1 immunotherapy. Dinaciclib, a potent CDK inhibitor of CDK1, 2, 5, 9 and 12, can induce apoptosis in various tumor cells as described above. Hossain et al. This combination therapy can induce T cell infiltration and DC activation, suggesting that combination therapy can improve anti-tumor immune response and lead to tumor regression.
In addition, in combination with anti-PD1 antibodies, Dinaciclib can induce immunogenic cell death ICD to convert tumor cells into endogenous vaccines [ 26 ]. Together, this study has paved a new path in solving the toxic and side-effect issues of pan-CDK inhibitors, thus increases the application possibility of pan-CDK inhibitors.
CDK4 and CDK6 are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. In a mouse tumor model study, Goel et al. In a recent study, Schaer et al. Further study indicated that Abemaciclib monotherapy can increase T cell inflammatory and delay tumor growth. Combination therapy with Abemaciclib and anti-PDL1 antibody can induce immunological memory and tumor elimination. These results suggested that combination therapy with Abemaciclib and anti-PDL1 antibody effectively stimulated both innate and adaptive immune response.
Taken together, combination therapy with Abemaciclib and anti-PDL1 antibody have presented a great potential in clinical application. Read our disclaimer for details. Last Update Posted : January 4, See Contacts and Locations. Study Description. Detailed Description:. MedlinePlus related topics: Breast Cancer. FDA Resources. Arms and Interventions. Trilaciclib administered IV over 30mins prior to chemotherapy on Day 1 and Day 8 of each day cycle.
Gemcitabine administered IV on Day 1 and Day 8 of each day cycle. Carboplatin administered IV on Day 1 and Day 8 of each day cycle. The subjects in the placebo arm will follow the same schedule as the trilaciclib arm, but will receive placebo instead of trilaciclib. Placebo administered IV over 30mins prior to chemotherapy on Day 1 and Day 8 of each day cycle.
Outcome Measures. Primary Outcome Measures : Effect on Overall Survival OS [ Time Frame: Cohort 1:From date of randomization up to 39 months ] Cohort 1 :To evaluate the effect of trilaciclib on overall survival OS compared with placebo in patients receiving first-line gemcitabine and carboplatin.
Occurrence of cytopenias, febrile neutropenia, hospitalization due to chemotherapy-induced myelosuppression, RBC and platelet transfusions, growth factor administration, and dose reductions and delays. To evaluate the effect of trilaciclib on progression-free survival PFS compared with placebo in patients receiving gemcitabine and carboplatin.
Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for radiation therapy. Patients should be recovered from the effects of radiation. Archival tumor tissue must be available or a fresh biopsy must be obtained, unless approved by the Medical Monitor.
Eastern Cooperative Oncology Group ECOG performance status of 0 or 1 Adequate organ function as demonstrated by normal laboratory values Exclusion Criteria: Prior treatment with gemcitabine in any setting. Receipt of any cytotoxic chemotherapy within 14 days prior to the first dose of study drugs. Known hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol Pregnant or lactating women Prior hematopoietic stem cell or bone marrow transplantation.
Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. Layout table for location contacts Contact: G1Therapeutics Clinical Contact clinicalinfo g1therapeutics. Hinkson Medstar. Lammers bmg.
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