Sara Karlovitch is an associate editor with Targeted Oncology. She received a duel degree in Journalism and Government and Politics from the University of Maryland. 

Sara Karlovitch

KB-0742, a CDK9 inhibitor designed for the treatment of 

-amplified solid tumors and non-Hodgkin lymphoma, has demonstrated a differentiated pharmacokinetic profile, according to interim results of a phase 1/2 clinical trial of the agent.

The phase 1/2 clinical trial (NCT04718675) is composed of a dose-escalation and dose-expansion parts. It has an estimated enrollment of 100 participants and an estimated study completion date of March 2024. The primary end points of the study are the incidence of adverse events, the number of participants with dose-limiting toxicities, and the recommended phase 2 dose. Secondary end points include maximal plasma concentration, time to maximal plasma concentration, area under the plasma concentration, progression-free survival, disease control rate, duration of disease control, overall response rate, and duration of response.

During part 1 of the open-label, randomized study, patients received escalating doses of KB-0742. During part 2, patients will receive the recommended phase 2 dose. Cohort A of part 2 will be made up of patients with relapsed or refractory solid tumors with evidence of MYC amplification or overexpression. Cohort B will be made up of patients with relapsed or refractory soft tissue sarcomas with evidence of transcription factor dysregulation.

Oral bioavailability and dose-proportion exposure was seen across the first 3 dose levels, according to the pharmacokinetic analysis. The terminal half-life of the agent was 24 hours among the 12 patients treated in the trial. Between day 1 and 10, an approximate 2 to 2.5-fold accumulation was seen. Further escalation is needed in order to reach the desired level of CDK9 inhibition.

“We are pleased with the early findings from this trial, which demonstrate that KB-0742 is showing a differentiated PK profile and a level of target engagement in patients that we had predicted based on our preclinical studies,” said Norbert Bischofberger, PhD, president and chief executive officer of Kronos Bio, in a press release. “These early data are encouraging, and we look forward to continuing the trial and establishing a recommended Phase 2 dose.”

In order to participate in the study, patients must be 18 years of age or older, have a confirmed diagnosis of either solid tumors or non-Hodgkin lymphoma which have failed, are intolerant to, or are considered ineligible for standard-of-care therapies, an ECOG performance status of 0 or 1, measurable disease, adequate bone marrow, and organ function, and must agree to use highly effective birth control.

Patients treated with any other anti-cancer therapy within 4 weeks of the first dose, a history of allogeneic transplantation within 6 months, active central nervous system involvement, an active infection requiring systemic antibiotics, known, active COVID-19 infection, clinically significant infection, or uncontrolled hypertension are not eligible to participants.

The study is currently recruiting in California, Missouri, Tennessee, and Texas.

Kronos Bio announces positive data from ongoing phase 1/2 trial of oral CDK9 inhibitor KB-0742. News release. Kronos Bio. November 29, 2021. Accessed November 30, 2021. https://bit.ly/3D7k8Xu.

A dose escalation and cohort expansion study of KB-0742 in participants with relapsed or refractory solid tumors or non-Hodgkin lymphoma. ClinicalTrials.gov. Accessed November 30, 2021. https://bit.ly/3d5Si3f

Articles

KB-0742 is currently being evaluated in a phase 1/2 clinical trial. The terminal half-life was found to be 24 hours. 

New CDK9 Inhibitor Shows Favorable Pharmacokinetic Profile in MYC-Amplified Solid Tumors

It is well known that patients with cancer who are infected with COVID-19 have worse outcomes than individuals without cancer. However, questions remain around specific prognostic factors.

An analysis of 455 Swiss patients looked at the outcomes and prognostic factors of patients with cancer who contract COVID-19. Cancer types represented in the analysis included breast (14%), lung (10%), prostate (6%), and myeloma (4%).

Nearly half, 45%, had non-curative disease and 23% of patients received systemic treatment within 3 months prior to COVID-19 diagnosis. In total, 63% were hospitalized for COVID-19, 47% required oxygen, and 9% required invasive ventilation.

Lead author Markus Joerger, MD, of the Medical Oncology and Hematology Department at Kantonsspital St. Gallen in St. Gallen, Switzerland, discussed the outcomes and prognostic factors of patients with cancer won contract COVID-19 in an interview with Targeted Oncology

TARGETED ONCOLOGY™: Can you give an overview research on the outcomes and prognostic factors of COVID-19 infection in cancer patients?

At the start of the pandemic, we realized that it would be important to have some data on the outcome of cancer patients [infected with COVID-19], because obviously, cancer patients are a group of people that are more vulnerable to COVID-19 infection. And so, what we did is we collected data from all cancer patients that had a symptomatic COVID infection over a 1-year period starting March 1, 2020. The majority of patients had a polymerase chain reaction confirmed COVID infection. All were symptomatic. And we just looked at prognostic factors.

Can you go into some of the results that you observed?

We had 455 patients. A slight majority was 65 or older. So, an elderly population, probably older than a standard population, if you do not look specifically at cancer. Then solid tumors versus hematologic tumors, that was the majority, 75% were solid tumors. And then thirdly, 50% were in a non-curative setting. And we also looked at previous treatment before the diagnosis of COVID within the 3-month time period before the diagnosis. A fifth of the patients received chemo, a fifth received targeted agents, and a minority of 7% received checkpoint inhibitors. Then we looked at comorbidity. Many patients had cardiovascular comorbidity, more than 50%. And close to 15%, had lung disease comorbidities.

This is just the characteristics of the population, but what is certainly more important is the outcome of the COVID infection. And these results were pretty dark so to say. More than 60%, 62% to be exact, were hospitalized for COVID. There is a footnote there in that some patients were already hospitalized, but probably all patients were hospitalized for the symptomatic COVID infection. Almost 50%, 47% to be exact, required oxygen. And, importantly, almost 40%, 34.6% to be exact, were admitted to the intensive care unit (ICU) and almost 10% required invasive ventilation. So pretty severe consequences.

And then of course, most importantly, COVID-19 mortality in all patients was 21.5%. In hospitalized patients, it was 31%. In patients that required oxygen, 41%, and in ICU patients, 56%. The overall mortality of more than 20% is clearly higher than what we know from the general population. Of course, this is not a clean comparison.

We looked a little bit at the specific treatment, but I think that is probably not that important. What is certainly important is that we did univariate and multivariate analysis to look at significant prognostic factors for the COVID-19 outcome. And here, there were basically no surprises. Oxygen requirement was a very heavy negative prognostic factor with a hazard ratio of 22. ICU admission, of course, also with a hazard ratio of 4.4. This is multivariate now, age 65 or older with a hazard ratio of 3.2. And the noncurative versus curative setting with a with a hazard ratio of 2.4. So, these were the significant multivariant negative prognostic factors. So, no surprises there. And in conclusion, on one hand, the severe outcome of COVID-19 in this patient population. It pretty comparable to other countries, though. That also interesting for us, because, in Switzerland, you have a centralized health care system. That somehow different than if you compare it to the UK, or to the US or many other countries. So, it was also interesting to understand whether a decentralized system would fare better or worse in the pandemic with regards to cancer patients. And that seems not to be the case.

Did patients with certain cancer types fair better than others?

We looked at that, and there are other studies that suggested that hematologic malignancies had somewhat worse outcomes, but we didn't see that now. And the numbers for very specific tumor types were too small to really have reliable insight into that. So, we did this analysis, but we didn't see that particular cancer types did particularly well or particularly bad.

Do you have any research planned for the future?

We are not directly using this data set, but upcoming data sets. And this topic is the success of vaccinations in cancer patients. There is already some insight into that from other countries, but also from our group and in our country that vaccines really do not work as good in cancer patients as in healthy, healthy people. And this is a big concern, and it is, of course, very important to tackle this issue.

Joerger M, Metaxas Y, Zaman K, et al. Outcome and prognostic factors of COVID-19 infection in cancer patients: Final results of SAKK 80/20. 

. 2021;32(5):1134-1135. doi: 10.1016/j.annonc.2021.08.1563

Markus Joerger, MD, discussed the outcomes and prognostic factors of patients with cancer won contract COVID-19 in an interview with Targeted Oncology.










ICU Admission, Oxygen Use Predict Outcomes in Patients With Cancer and COVID-19

The first patient has been dosed in the phase 3 TROPION-Breast01 study, which is evaluating the efficacy and safety of datopotamab deruxtecan (Dato-DXd; DS-1062) for the treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, according to a press release by Daiichi-Sankyo.

Dato-DXd is an investigation TROP2 directed antibody drug conjugate. High TROP2 expression is an unfavorable prognostic factor in overall survival. Currently, no TROP2 directed therapies are approved for HR=positive, HER2

"Most patients with HR-positive, HER2-negative metastatic breast cancer will inevitably progress on available treatments, including hormonal therapy and standard of care chemotherapy. In this setting, the unmet need is high, and new therapeutic approaches are necessary to delay disease progression and extend survival," said Cristian Massacesi, MD, chief medical officer and oncology chief development officer, AstraZeneca, in the press release. "The TROPION-Breast01 trial will evaluate whether datopotamab deruxtecan may be a more effective treatment than chemotherapy for patients with previously treated HR positive, HER2 negative advanced breast cancer previously treated with one to two lines of chemotherapy."

The phase 3, randomized, parallel assignment, open-label study (NCT05104866) has a target enrollment of 700 participants. The estimated study completion date is July 21, 2025. The primary end points are progression-free survival and overall survival. Secondary end points include objective response rate, duration of response, disease control rate, time to first subsequent therapy, time from randomization to second progression or death, pharmacokinetics, and immunogenicity.

During the study, patients will be randomized to receive either Dato-DXd or the investigator’s choice of chemotherapy.

In order to participate in the study, patients must be 18 years of age or older, or 20 years of age or older if they live in Japan. Additionally, patients must have a confirmed diagnosis of inoperable or metastatic HR-positive, HER2-negative breast cancer, progressed on or are not eligible for endocrine therapy, have an ECOG performance status of 0 or 1, at least 1 measurable lesion, adequate organ and bone marrow function, and a minimum life expectancy of 12 weeks at screening.

Patients with a history of another primary malignancy, persistent toxicities caused by previous anticancer therapies, uncontrolled infection, known active or uncontrolled hepatitis B or C infection, known HIV infection, uncontrolled or significant cardiac disease, clinically severe pulmonary, leptomeningeal carcinomatosis, clinically significant corneal disease, concurrent use of hormonal therapy, or have undergone a major surgical procedure within 3 weeks of the first study dose are not eligible to participate.

"There are no TROP2 directed therapies currently approved for HR-positive, HER2-negative breast cancer and we are encouraged by the emerging clinical profile of datopotamab deruxtecan in patients with breast cancer," said Gilles Gallant, BPharm, PhD, FOPQ, senior vice president, global head, oncology development, oncology R&D, Daiichi Sankyo, in the press release. "TROPION-Breast01 is the first pivotal trial of datopotamab deruxtecan in breast cancer and the third pivotal study in our clinical development program, underscoring our efforts to accelerate development of this TROP2 directed ADC in breast and lung cancer."

The study is currently recruiting at 129 locations across the United States. Although the study will be global, sites in Canada, Argentina, Brazil, China, Europe, and Asia are not yet recruiting patients.

TROPION-Breast01 phase 3 trial of datopotamab deruxtecan initiated in patients with hormone receptor positive, HER2 negative metastatic breast cancer. News release. Daiichi-Sankyo. November 18, 2021. Accessed November 23, 2021. https://bit.ly/3FLFQ5fla

A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-Positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). ClinicalTrials.gov. Accessed November 23, 2021. c.

The TROPION-Breast01 study aims to enroll 700 patients to determine the safety and efficacy of datopotamab deruxtecan in patients with HR-positive, HER2-negative breast cancer. 

Investigators Dose Datopotamab Deruxtecan in First Patient With HR+ /HER2- Breast Cancer 

The first patient has been dosed in the phase 2 basket trial of milademetan for 

-amplified advanced solid tumors, according to a press release by Rain Therapeutics.

 inhibitor that is meant for the treatment of 

-amplified solid tumors. A phase 1 clinical trial found that the agent demonstrated antitumor activity in an 

-amplified subtype of liposarcoma and other solid tumors.

“The opening of our phase 2 basket trial is a significant step forward in leveraging the safety profile of milademetan for patients with advanced tumors that exhibit wild-type p53 and amplified MDM2 who do not respond, or stop responding, to standard-of-care therapy,” said Richard Bryce, MBChB, chief medical officer of Rain Therapeutics in the press release.

The interventional, open-label study (NCT05012397) has a target enrollment of 65 participants and an estimated study completion date of August 2024. The primary end point is overall response rate. Secondary end points include duration of response, progression-free survival, growth modulation index, disease control rate, and overall survival.2

During the study, all patients will receive milademetan at a dose of 260 mg daily on days 1 to 3 and 15 to 17 of each 29-day cycle. Therapy will be continued until disease progression, unacceptable toxicity, or until other treatment discontinuation criteria are met. Treatment may be continued after progression occurs if the investigator determines the patient is experiencing clinical benefit.

In order to participate in the study, patients must be 18 years of age or older, have a confirmed diagnosis of a cancer that is locally advanced or metastatic solid tumor, measurable tumor lesions, have received all standard therapy that is appropriate for their tumor type and disease stage, have recovered from any clinical relevant toxic effects, an ECOG performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function.

Patients who received prior treatment with an MDM2 inhibitor, have a diagnosis of well-differentiated/dedifferentiated liposarcoma or initial sarcoma, a primary malignancy requiring systemic antineoplastic treatment within the past 2 years, a primary brain tumor, untreated brain metastases, gastrointestinal conditions that could affect the absorption of milademetan, known HIV infection, major surgery ≤ 3 weeks of the first dose of the study drug, curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy, or uncontrolled or significant cardiovascular disease are not eligible to participate.

“The Rain team has worked extraordinarily hard to now commence our second clinical trial for milademetan,” said Avanish Vellanki, chief executive officer of Rain Therapeutics, in the press release. “The MANTRA-2 study reflects our precision oncology focus to base our development strategy on the underlying biological drivers in cancer, now across a tumor-agnostic clinical trial. We have also identified a level of gene amplification of MDM2 that we believe will select for patients most likely to benefit.”

The study is currently recruiting at The University of Texas MD Anderson Cancer Center.

1.Rain Therapeutics doses first patient in phase 2 basket trial of milademetan for MDM2-amplified advanced solid tumors (MANTRA-2). News release. Rain Therapeutics. November 19, 2021. Accessed November 23, 2021. https://bit.ly/3CHTG6B

2.Milademetan in advanced/metastatic solid tumors. ClinicalTrials.gov. Accessed November 23, 2021. https://bit.ly/3oRIZJL

Milademetan, an MDM2-inhibitor, has already shown preliminary antitumor efficacy in solid tumors. 

Milademetan Treatment Begins for MDM2-Mutated Solid Tumors in Phase 2 Basket Trial

Venetoclax with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (Rituxan; EPOCH-R) showed an acceptable safety profile and preliminary activity in patients with aggressive B-cell lymphoma, according to a results of a phase 1 study published in the 

Currently, dose-adjusted EPOCH-R is a frontline treatment for aggressive B-cell lymphomas. Approximately two-thirds of patients achieve remission with initiation chemoimmunotherapy. However, high-risk clinical and biological features predict an adverse outcome with standard therapy for many patients. This highlights a need for improved first-line treatments. One such factor is the genetic rearrangement or overexpression of the anti-apoptotic protein BCL-2, which is associated with a suboptimal response to front-line chemoimmunotherapy. Venetoclax is an oral inhibitor of BCL-2 that is approved by the FDA for chronic lymphocytic leukemia and has been studied in combination with chemotherapy in non-Hodgkin lymphomas, including diffuse large B-cell lymphoma.

The phase 1 study (NCT03036904) has an actual enrollment of 31 participants. Primary end points include the determination of maximal tolerated dose and dose limiting toxicities. Secondary end points include incidence and severity of adverse events, overall response rate, complete response rate, event-free survival, progression-free survival, and overall survival.

During the study, all patients received 6, 21-day cycles of the experimental combination. Venetoclax was administered on days 1 through 10, with the exception of cycle 1, where it was started on day 3 and continued through day 12. Three dose levels of venetoclax were tested: 400 mg, 600 mg, and 800 mg.

Between February 2017 and June 2019, 34 patients were screened for eligibility and 31 were enrolled. Thirty went on to receive the experimental combination and 19 completed all 6 cycles. Reasons for withdrawal included withdrawal of consent (5), persistent cytopenias (3), intracranial hemorrhage (1), chronic back pain (1), and death due to sepsis (1).

The median age of patients was 64 (range, 51.6-69.4), 50% were female, 80% were non-Hispanic, and 77% were white. Ann Arbor stages included II (23%), III (20%), and IV (57%). One extranodal site was seen in 53% of patients and 57% had high-intermediate or high prognoses. Diagnoses included double-hit lymphoma (50%), diffuse large B-cell lymphoma not otherwise specified (30%), primary mediastinal large B-cell lymphoma (7%), high-grade B-cell lymphoma not otherwise specified (7%), and transformed indolent non-Hodgkin lymphoma (7%). Rearrangements included 

 Immunohistochemistry expressions included 

The ORR was 96.7% (95% CI, 82.8-99.9), and the complete response rate was 93.8% (95% CI, 77.9-99.2). Additionally, 1 partial response was observed. The estimated 2-year PFS and EFS were both 83% (95% CI, 63.8-92.5). The estimated 2-year OS was 89.9% (95% CI, 71.8-96.6). The 12-month EFS was 86.4% (95% CI, 67.7-94.7%). Five patients had a progression-free survival event and 3 patients died.

In patients with double-hit lymphoma, the ORR was 93.3% (95% CI, 68.1-99.8), with a complete response rate of 86.7% (95% CI, 59.5-98.3). The estimated 2-year PFS and EFS were both 65% (95% CI, 35.1-83.7). The estimated 2-year OS was 79.4% (95% CI, 48.8-92.9).

No dose-limiting toxicities were observed at dose levels 1 or 2. At dose level 2, 1 of the 6 patients (17%), had a dose-limiting toxicity of grade 4 thrombocytopenia. The maximum tolerated dose was 800 mg for 10 days. Six-hundred milligrams was selected as the recommended phase 2 dose due to better tolerability throughout the entire treatment duration.

One grade 5 incidence of sepsis was reported. Grade 4 adverse events included lymphocyte count decrease (3%), platelet count decrease (53%), white blood cell count decrease (67%), neutrophil count decrease (67%), hypokalemia (7%), and nausea (3%).

“The addition of venetoclax to dose-adjusted EPOCH-R or R-CHOP in patients with double-hit lymphoma and double-expressor lymphoma is now being evaluated in Alliance 051701, a randomized phase 2/3 trial (NCT03984448). Although it will be necessary to minimize toxicity and maximize the tolerability of this regimen, the encouraging results in our phase 1 trial, particularly in patients with double-hit lymphoma and double-expressor lymphoma, indicate that venetoclax plus dose-adjusted EPOCH-R is a combination therapy that merits further investigation,” wrote study authors.

Rutherford S, Abramson J, Bartlett N, et al. Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. 

2021;8:e818–27 doi: 10.1016/S2352-3026(21)00273-8.

Venetoclax in combination with EPOCH-R is safe and shows preliminary efficacy in patients with aggressive B-cell lymphoma. 

Venetoclax With EPOCH-R Appears Safe in Aggressive B-Cell Lymphoma 

The FDA has accepted the biologics license application for betibeglogene autotemcel (beti-cel), a one-time gene therapy for patients with B-thalassemia who require regular red blood cell transfusions, according to a press release by Bluebird bio, Inc.

Beti-cel’s mechanism of action is adding functional copies of a modified form of B-globin in a patient’s stem cells in order to correct deficiently of adult hemoglobin. Once the B-globin gene is acquired at certain levels, it may eliminate the need for transfusions.

“For too long, people with β-thalassemia who rely on regular transfusions have had to live with extraordinary burdens associated with their disease. beti-cel works uniquely to help patients produce adult hemoglobin at normal or near-normal levels, which can eliminate their need for chronic transfusions and chelation that only temporarily relieve the symptoms of anemia and are associated with serious health risks and reduced quality of life,” said Anne-Virginie Eggimann, chief regulatory officer, of bluebird bio, in a press release. “This BLA acceptance represents the culmination of contributions from many, including the patients involved in the clinical program, their caregivers, and the study investigators. We look forward to working closely with the FDA to bring this treatment to patients in need.”

The application is supported by data from 5 separate studies, the phase 3 Northstar-2 (NCT02906202) and Northstar-3 (NCT03207009) studies, and the phase 1/2 studies Northstar (NCT01745120) and HGB-205 (NCT02151526), and the long-term LTF-303 (NCT02633943). As of March 9, 2021, 63 pediatric, adolescent, and adult patients. Additionally, long-term efficacy and safety results are available in 2 patients who more than 7 years of follow-up.

In the phase 3 studies, 89% of evaluable patients, including pediatric patients and those with the most severe genotypes, achieved transfusion independence. Transfusion independence was defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average hemoglobin of at least 9 g/dL.

“The FDA’s acceptance of our BLA for beti-cel brings us one step closer to potentially providing a one-time treatment that can address the underlying cause of β-thalassemia and offer patients freedom from regular transfusions,” said Andrew Obenshain, chief executive officer of bluebird bio, in a press release. “It’s also a critical milestone for bluebird bio as an independent severe genetic disease company. We are moving forward with great discipline and exceptional care to deliver on our commitments to patients and achieve our near-term goal of launching three first-in-class gene therapies in the United States.”

A prescription drug user fee act goal data of May 20, 2022 has been set. Additional data will be presented at the 63rd American Society of Hematology Annual Meeting and Exposition.

bluebird bio announces FDA priority review of biologics license application for beti-cel gene therapy for patients with β-thalassemia who require regular red blood cell transfusions. News release. bluebird bio. November 22, 2021. Accessed November 23, 2021. https://bit.ly/32trmIT

The newly accepted FDA approval application for betibeglogene autotemcel is supported by 5 studies of the agent across all ages of patients. Eighty-nine percent of evaluable patients achieved transfusion independence. 