Oncternal Therapeutics

A CIRM-funded therapy for a deadly blood cancer gets approval for Phase 3 clinical trial

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Michael Wang, MD (right) of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center will lead the Phase 3 clinical

Oncternal Therapeutics, Inc. is celebrating an encouraging milestone at the start of the new year following a successful End-of-Phase 2 meeting with the FDA. 

Specifically, the FDA agreed on key elements of the company’s potentially pivotal Phase 3 clinical trial of zilovertamab, which offers potential treatment advantages to patients suffering from relapsed or refractory mantle cell lymphoma (MCL). Zilovertamab (previously called cirmtuzumab because it was developed with CIRM funding) is the company’s investigational anti-ROR1 monoclonal antibody. 

Mantle cell lymphoma is an aggressive form of blood cancer that develops when white blood cells, which are a key component of our immune system and help fight infections, grow out of control. 

The California Institute for Regenerative Medicine (CIRM) funded an earlier-stage trial conducted by Oncternal Therapeutics in collaboration with UC San Diego. 

The Phase 3 clinical trial will be led by Dr. Michael Wang, of the Department of Lymphoma & Myeloma at MD Anderson Cancer Center. The trial will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo. All patients will continue receiving oral ibrutinib.  

The study (ZILO-301) will be conducted internationally in at least 50 centers experienced in treating MCL, and is expected to begin in the second quarter of 2022.  

The researchers hope the treatment will lead to progression-free survival for patients getting zilovertamab and that this will lead to FDA approval of the therapy. 

The company is also planning to conduct study ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301. 

Read the full release of the study here and be sure to follow the Stem Cellar blog for more updates on the clinical trial.  

Stem Cell Agency Board Invests in Therapy Targeting Deadly Blood Cancers

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Dr. Ezra Cohen, photo courtesy UCSD

Hematologic malignancies are cancers that affect the blood, bone marrow and lymph nodes and include different forms of leukemia and lymphoma. Current treatments can be effective, but in those patients that do not respond, there are few treatment options. Today, the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investing $4.1 million in a therapy aimed at helping patients who have failed standard therapy.

Dr. Ezra Cohen, at the University of California San Diego, and Oncternal Therapeutics are targeting a protein called ROR1 that is found in B cell malignancies, such as leukemias and lymphomas, and solid tumors such as breast, lung and colon. They are using a molecule called a chimeric antigen receptor (CAR) that can enable a patient’s own T cells, an important part of the immune system, to target and kill their cancer cells. These cells are derived from a related approach with an antibody therapy that targets ROR1-binding medication called Cirmtuzumab, also created with CIRM support. This CAR-T product is designed to recognize and kill cancer stem cells that express ROR1.

This is a late-stage preclinical project so the goal is to show they can produce enough high-quality cells to treat patients, as well as complete other regulatory measures needed for them to apply to the US Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in people.

If given the go-ahead by the FDA the therapy will target patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).  

“CAR-T cell therapies represent a transformational advance in the treatment of hematologic malignancies,” says Dr. Maria T. Millan, CIRM’s President and CEO. “This approach addresses the need to develop new therapies for patients whose cancers are resistant to standard chemotherapies, who have few therapeutic options and a very poor chance or recovery.”

CIRM-funded trial for blood cancer releases promising new data

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A CIRM-funded trial conducted by Oncternal Therapeutics in collaboration with UC San Diego released an interim clinical data update for patients with mantle cell lymphoma (MCL), a type of blood cancer.

The treatment being developed involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the blood cancer and makes it more vulnerable to anti-cancer drugs.

Here are the highlights from the new interim clinical data:

  • Patients had received a median of two prior therapies before participating in this study including chemotherapy; autologous stem cell transplant (SCT); autologous SCT and CAR-T therapy; autologous SCT and allogeneic SCT; and ibrutinib with rituximab, a different type of antibody therapy.
  • 6 of the 12 patients in the trial experienced a Complete Response (CR), which is defined as the disappearance of all signs of cancer in response to treatment.
  • All six CRs are ongoing, including one patient who has remained in CR for more than 21 months past treatment.
  • Four of the six patients achieved CRs within four months on the combination of cirmtuzumab and ibrutinib.
  • Of the remaining 6 patients, 4 experienced a Partial Response (PR), which is defined as a decrease in the extent of the cancer in the body.
  • The remaining two patients experienced Stable Disease (SD), which is defined as neither an increase or decrease in the extent of the cancer.

The full interim clinical data update can be viewed in the press release here.

Four CIRM Funded Trials Release Results at 2019 ASH Meeting

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With more than 17,000 members from nearly 100 countries, the American Society of Hematology (ASH) is an organization composed of clinicians and scientists around the world working to conquer various blood diseases. Currently, they are having their 61st Annual ASH Meeting to highlight some of the exciting work going on in the field. Four of our CIRM funded trials have released promising results at this conference and we wanted to take the opportunity to highlight them below.

Sangamo Therapeutics

Sangamo Therapeutics is conducting a CIRM-funded clinical trial for beta-thalassemia, a severe form of anemia caused by mutations in the hemoglobin gene. The therapy Sangamo is testing takes a patient’s own blood stem cells and, using a gene-editing technology called zinc finger nuclease (ZFN), provides a functional copy of the hemoglobin gene. These modified cells are then given back to the patient. The company announced preliminary results from their first three patients treated. in the clinical trials at the ASH 2019 Conference as well.

Some of the highlights are the following:

  • The first three patients experienced prompt hematopoietic reconstitution, meaning that their supply of blood stem cells was restored.
  • The first three patients experienced no clonal hematopoiesis, meaning that the blood stem cells did not create cells with mutations in the DNA
  • Additional study results are expected in late 2020 once enrollment is complete and all six patients have longer follow-up

You can read more detailed results regarding the first three patients in the press release.

Forty Seven, Inc.

In another CIRM funded trial, Forty Seven, Inc. is testing a treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The treatment involves an antibody called magrolimab in combination with the chemotherapy drug azacitidine. Cancer cells express a signal that send a “don’t eat me” message to white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect these evasive cancer cells. The goal is to use both magrolimab and azacitidine to make the cancer stem cells vulnerable to being attacked and destroyed by the immune system.

Of the 46 patients evaluated, 24 patients had untreated higher-risk MDS and 22 patients had untreated AML. None of the patients were eligible for treatment with chemotherapy.

In higher-risk MDS, the overall response rate (ORR), which is the proportion of patients in a trial whose tumor is destroyed or significantly reduced by a treatment, was 92%.

Within this group of patients with an ORR, the following was observed:

  • 12 patients (50%) achieved a complete response (CR), meaning that they experienced a disappearance of all signs of cancer in response to treatment.
  • Two patients (8%) achieved hematologic (blood) improvement. 
  • Additionally, two patients (8%) achieved stable disease, meaning the cancer is neither increasing nor decreasing in extent or severity.

In untreated AML, the ORR was 64% and the following was observed within this group patients with an ORR:

  • Nine patients (41%) achieved a CR
  • Three patients (14%) achieved a CR with an incomplete blood count recovery (CRi)
  • One patient (5%) achieved a morphologic leukemia-free state (MLFS), which is defined as the disappearance of all cells with morphologic characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
  • Seven patients (32%) achieved stable disease (SD)

The median time to response among MDS and AML patients treated with the combination was 1.9 months.

More details regarding these results are available via the news release.

Oncternal Therapeutics

Onceternal Therapeutics, which is conducting a CIRM-funded trial for a treatment for lymphoma and leukemia, presented results at the 2019 ASH Meeting. The treatment involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs.

Some of the results presented are summarized as follows:

  • Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
  • One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR.
  • Five patients had stable disease.
  • The total clinical benefit rate was 100%.
  • None of the patients died or saw their disease progress.
  • Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on the combination therapy.
  • The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib by itself was blunted with the addition of cirmtuzumab, and leukemic cell counts returned toward baseline and normal levels rapidly.

You can read more about these results in the official press release.

Rocket Pharmaceuticals

Last, but not least, Rocket Pharmaceuticals presented results at the 2019 ASH Conference related to a CIRM-funded trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare pediatric disease caused by a mutation in a specific gene that affects the body’s ability to combat infections. As a result, there is low expression of neutrophil (CD18). The company is testing a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.  

Here are some of the highlights from the presentation:

  • Initial results from the first pediatric patient treated demonstrate early evidence of safety and potential effectiveness. 
  • The patient exhibited early signs of engraftment
  •  The patient also displayed visible improvement of multiple disease-related skin lesions after receiving therapy
  •  No safety issues related to administration have been identified

More detailed results on this trial are available via the news release.

Encouraging Progress for Two CIRM Supported Clinical Trials

/ Yimy Villa / 4 Comments

This past Wednesday was Stem Cell Awareness Day, a day that is meant to remind us all of the importance of stem cell research and the potential it has to treat a wide variety of diseases. On this day, we also released an independent Economic Impact Report that showed how $10.7 Billion (yes, you read that right) was generated as a direct result of the the legacy we have built as a state agency that funds groundbreaking research.

Aside from the monetary incentive, which is an added bonus, the research we fund has made encouraging progress in the scientific field and has demonstrated the positive impact it can have on various disease areas. This week, two clinical trials supported by CIRM funding have released very promising updates.

Duchenne Muscular Dystrophy

Capricor Therapeutics, Inc. has presented positive results for a clinical trial related to a treatment for duchenne muscular dystrophy (DMD), a genetic disorder. DMD leads to progressive muscle degeneration and weakness due to its effect on a protein called dystrophin, which helps keep muscle cells intact.

The treatment that Capricor is testing is called CAP-1002 and consists of a unique population of cells that contain cardiac progenitor cells, a type of stem cell, that help encourage the regeneration of cells. CIRM funded an earlier clinical trial for this treatment.

The early results of this current trial describe how teens and young men in the advanced stages of DMD saw improvements in skeletal, lung, and heart measurements after receiving multiple doses of the treatment.

In a news release, Dr. Linda Marban, Chief Executive Officer of Capricor, expresses optimism for this clinical trial by saying,

“We are very pleased that the interim analysis from this double-blind placebo-controlled study, has demonstrated meaningful improvements across three clinically relevant endpoints in older patients with limited remaining treatment options.”

In the same news release, Dr. Craig McDonald, the national principal investigator for the trial, echoes the same sentiment by stating,

“The results from this trial to date are very promising in that the cells appear to positively impact skeletal, pulmonary and cardiac assessments in older DMD patients who have few, if any, remaining treatment options. We are eager to meet with the FDA to discuss the next steps for this promising program.”

Mantle Cell Lymphoma

Additionally, Oncternal Therapeutics has decided, because of positive results, to open an expansion of its CIRM-funded clinical trial aimed at treating patients with mantle cell lymphoma (MCL). The treatment involves an antibody called cirmtuzumab, named after us, in combination with a drug called ibrutinib.

The preliminary results were from the first six patients with MCL that were treated in the trial. One patient with MCL, who had relapsed following an allogeneic stem cell transplant, experienced a confirmed complete response (CR) after three months of cirmtuzumab plus ibrutinib treatment. This complete response appears to be sustained and has been confirmed to be ongoing after completing 12 months of the combination treatment. A second confirmed complete response occurred in a patient who had progressive disease after failing several different chemotherapy regimens, bone marrow transplant and CAR-T therapy. 

In a news release, Dr. Hun Lee, an investigator in the trial, states that,

“It is encouraging to see that the drug has been well tolerated as well as the early signal of efficacy of cirmtuzumab with ibrutinib in MCL, particularly the rapid and durable complete responses of the heavily pre-treated patients after three months of therapy, which is an unusually fast response in this patient population.”

CIRM-funded clinical trial shows encouraging results for patients with chronic lymphocytic leukemia & mantle cell lymphoma

/ Yimy Villa / Leave a comment
Illustration courtesy of Oncternal Therapeutics

I often joke that my job here at CIRM is to be the official translator for the stem cell agency. I have to translate complex science into everyday English that people without a science background – that includes me – can understand.

Think I’m joking? Try making sense of this.

See what I mean. If you are a scientist this is not only perfectly clear, it’s also quite exciting. But for the rest of us……..

Actually, it is really quite exciting news. It’s about a CIRM-funded clinical trial being run by Oncternal Therapeutics to treat people with chronic lymphocytic leukemia (CLL), a kind of cancer where our body makes too many white blood cells. The study is using a combination therapy of Cirmtuzumab (a monoclonal antibody named after us because we helped fund its development) and ibrutinib, a conventional therapy used to treat cancers like CLL.

Cirmtuzumab recognizes and then attaches itself to a protein on the surface of cancer stem cells that the cancer needs to survive and spread. This attachment disables the protein (called ROR1) which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs like ibrutinib.

In this Phase 1/2 clinical trial 12 patients were given the combination therapy for 24 weeks or more, making them eligible to determine how effective, or ineffective, the therapy is:

  • 11 of the 12 patients had either a partial response – meaning a reduction in the amount of detectable cancer – or a complete response to the treatment – meaning no detectable cancer.
  • None of the patients saw their cancer spread or grow
  • Three of the patients completed a year of treatment and they all showed signs of a complete response including no enlarged lymph nodes and white blood cell counts in the normal range.  

The combination therapy is also being used to treat people with Mantle Cell Lymphoma (MCL), a rare but fast-growing form of blood cancer. The results from this group, while preliminary, are also encouraging. One patient, who had experienced a relapse following a bone marrow transplant, experienced a complete response after three months of cirmtuzumab and ibrutinib.  

The data on the clinical trial was presented at a poster session (that’s the poster at the top of this blog) at the annual meeting of the American Society of Clinical Oncology.

In a news release Dr. James Breitmeyer, the President & CEO of Oncternal, said the results are very encouraging:  

“These data presented today, taken together with an earlier Phase 1 study of cirmtuzumab as a monotherapy in relapsed/refractory CLL, give us increased confidence in the potential for cirmtuzumab as a treatment for patients with ROR1-expressing lymphoid malignancies, particularly in combination with ibrutinib as a potential treatment for patients with CLL and MCL. We believe that the data also help to validate the importance of ROR1 as a therapeutic target,”

A cancer therapy developed at a CIRM Alpha Stem Cell Clinic tests its legs against breast cancer

/ Pallavi Penumetcha / 1 Comment

Breast cancer cells

Three-dimensional culture of human breast cancer cells, with DNA stained blue and a protein on the cell surface membrane stained green. Image courtesy The National Institutes of Health

A Phase 1 clinical trial co-sponsored by CIRM and Oncternal Therapeutics, has started treating patients at UC San Diego (UCSD). The goal of the trial is to test the safety and anti-tumor activity of the Oncternal-developed drug, cirmtuzumab, in treating breast cancer.

Breast cancer is the second most common cancer to occur in women, regardless of race or ethnicity. More than 260,000 new cases are expected to be diagnosed this year in the United States alone. Typically, breast cancer cases are treated by a combination of surgery to remove the tumor locally, followed by some kind of systemic treatment, like chemotherapy, which can eliminate cancer cells in other parts of the body. In certain cases, however, surgery might not be a feasible option. Cirmtuzumab may be a viable option for these patients.

The drug acts by binding to a protein called ROR1, which is highly abundant on the surface of cancer cells. By blocking the protein Cirmtuzumab is able to promote cell death, stopping the cancer from spreading around the body.

Because ROR1 is also found on the surface of healthy cells there were concerns using cirmtuzumab could lead to damage to healthy tissue. However, a previous study revealed that using this kind of approach, at least in a healthy non-human primate model did not lead to any adverse clinical symptoms. Therefore, this protein is a viable target for cancer treatment and is particularly promising because it is a marker of many different types of cancers including leukemia, lung cancer and breast cancer.

Phase 1 clinical trials generally enroll a small number of patients who have do not have other treatment options. The primary goals are to determine if this approach is safe, if it causes any serious side-effects, what is the best dosage of the drug and how the drug works in the body. This clinical trial will enroll up to 15 patients who will receive cirmtuzumab in combination with paclitaxel (Taxol), a vetted chemotherapy drug, for six months.

Earlier this year, a similar clinical trial at UCSD began to test the effectiveness a of cirmtuzumab-based combination therapy to treat patients with B-cell cancers such as chronic lymphocytic leukemia. This trial was also partially funded by CIRM.

In a press release, Dr. Barbara Parker, the co-lead on this study states:

“Our primary objective, of course, is to determine whether the drug combination is safe and tolerable and to measure its anti-tumor activity. If it proves safe and shows effectiveness against breast cancer, we can progress to subsequent trials to determine how best to use the drug combination.”